Increased physical performance and reduced fatigue after personalised physiotherapy and nutritional counselling in long COVID

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Personalised nutritional counselling and physiotherapy could provide a synergistic effect to alleviate these symptoms. However, there is a lack of evidence of the feasibility and effectiveness of such personalised multimodal therapy (PMT) including both nutrition and physiotherapy. Methods In this pilot study, 65 participants were randomised into either standard physiotherapy or the PMT. Nutritional counselling focussed on tailoring the energy and protein intake to the individual needs based on indirect calorimetry and nutritional assessments. Personalised physiotherapy focused on symptom-contingent pacing. The aim was to evaluate the feasibility in light of a randomised controlled trial (RCT) and to assess the effectiveness of the PMT compared to standard physiotherapy. Effectiveness outcomes (1-minute sit-to-stand test (1-MSTS), 6-minute walk test (6-MWT), and the Multidimensional Fatigue Inventory (MFI-20)) were assessed after 6, 12 and 18 weeks. Descriptive statistics and sample size calculations were performed. Results We observed an advancement in both groups, however, the PMT group showed a significant improvement, for 1-MST, 6-MWT and physical fatigue at 18 weeks. Participant specific trajectories suggest a growing estimated difference between groups throughout the trial. To prove these interesting finding, 181 participants should be recruited in a RCT. Study feasibility was proven. Conclusions The study revealed a positive trend for improved physical function and reduced fatigue in adults with long COVID after combined nutritional counselling and physiotherapy. A large-scale RCT is needed to prove the effectiveness, but the current results are hopeful. Health sciences/Medical research/Clinical trial design/Randomized controlled trials Health sciences/Health care/Therapeutics/Nutrition therapy Health sciences/Health care/Therapeutics/Rehabilitation Figures Figure 1 Figure 2 Figure 3 Figure 4 Figure 5 Plain language summary Fatigue and difficulty recovering from exercise can be present 12 weeks after COVID-19 without additional illness. It is not clear how to improve these symptoms. We tested, in one group, if adjusting the participants' diet based on measurements and food diary analysis, combined with physiotherapy could help relieve these symptoms. A second group received standard physiotherapy. The study found that those who received both nutritional counselling and physiotherapy could walk further, perform more sit-to-stand repetitions, and were less tired after 18 weeks, while the standard physiotherapy group did not improve as much. These results suggest that dietitians and physiotherapists can adjust their approach. A larger study is needed to confirm the benefits of this approach. Introduction The Severe Acute Respiratory Syndrome Coronavirus (SARS-CoV-2) has led to over 775 million reported coronavirus disease 2019 (COVID-19) cases as of mid-August 2024 1 . Many COVID-19 survivors experience post-acute and long-term health effects, referred to as post-COVID-19 condition or “long COVID”, as defined by the World Health Organisation (WHO) 2 . A recent review estimates a cumulative global incidence of long COVID of over 400 million individuals 3 . Most diagnoses are seen in individuals aging 36–50 years and non-hospitalised patients with a mild acute illness 4 , 5 . The symptoms associated with long COVID are diverse and include general symptoms (e.g., fatigue, post-exertional malaise (PEM), and cognitive difficulties), as well as specific symptoms affecting respiratory, cardiovascular, musculoskeletal, neurological and digestive systems 6 – 10 . To date, there are no effective treatments. As long COVID is a multisystemic disease, the WHO guideline on the clinical management of COVID-19 emphasizes the need for multidisciplinary rehabilitation 11 . However, the effectiveness of comprehensive rehabilitation for long COVID has yet to be confirmed through randomized controlled trials (RCT) 12 . Nutrition plays a role in the prevention and management of obesity and type 2 diabetes, which are risk factors for COVID-19 13–16 . During the acute phase of COVID-19, symptoms such as nausea, diarrhoea, anorexia, anosmia and ageusia lead to a reduced nutritional intake 17 – 19 . Combined with the increased nutritional need caused by fever or critical illness, this leads to an increased risk of malnutrition and loss of muscle mass 19 , 20 . In long COVID, gastro-intestinal symptoms include loss of appetite, nausea and vomiting, abdominal pain, diarrhoea, constipation, heartburn, dysphagia, gastroparesis, altered bowel mobility and irritable bowel syndrome 21 – 23 . Symptoms like fatigue and PEM lead to reduced physical activity 24 , increasing the risk for negative body composition changes, such as increase of body weight and fat mass, and loss of muscle mass 25 . Long COVID is also linked with the new onset of comorbidities such as dyslipidaemia, insulin resistance or diabetes, hypertension, and kidney or liver issues 26 , 27 . Lifestyle interventions, including nutritional counselling, are part of the management of these conditions. Nutritional interventions address deficiencies and support metabolic processes, potentially improving energy levels 28 , 29 , which can be of interest for the management of fatigue or PEM. Moreover, a patient-centred approach by a registered dietitian can address personal factors that influence the nutritional intake, such as food preferences, financial factors, self-image, disordered eating, and eating behaviours (such as preparation, portions etc.). Current nutritional research in the long COVID population is of low evidence 30 . Additionally, most studied nutritional interventions are only performed in previously hospitalized or critically ill COVID-19 patients, and these studies usually focus on nutritional supplements 30 . Evidence is lacking for patient-centred nutritional counselling, with targeted caloric and macronutrient goals, as part of a multidisciplinary rehabilitation 30 . Physical exercise enhances functioning and reduces fatigue in other conditions 31 . Systematic reviews and meta-analyses show that physical rehabilitation interventions are potential therapeutic strategies and can be applied as routine clinical practice 31 , 32 . However, given the multisystem factor and the variability in symptoms, not all patients will benefit the same on given therapy. For example, for individuals suffering from PEM physical exercise is considered harmful in some cases 5 . Therefore, personalised therapy is necessary. This highlights the need for further research, particularly to investigate additional treatments that could leverage and enhance the beneficial effects of physical exercises. Our hypothesis is that nutritional counselling and physiotherapy provide a synergistic effect, offering a strategy to alleviate long COVID symptoms. This is the first study to combine comprehensive personalised nutrition and physiotherapy in adult individuals with long COVID. Due to the lack of research on such a personalised multimodal therapy (PMT) in the long COVID population, we performed a pilot study to prepare for a large-scale RCT. The goal of this pilot was to assess the feasibility of the PMT and to gain a better understanding of the effectiveness of the PMT compared to standard physiotherapy alone. We observed an advancement in both groups, however, the PMT group clearly showed a significant improvement, for 1-MST, 6-MWT and physical fatigue at 18 weeks. Participant specific trajectories suggest a growing estimated difference between groups throughout the trial. Generally, the study was found feasible. To show a minimally clinically important difference in a large-scale RCT, 181 participants should be recruited. Methods The study protocol is registered at ClinicalTrials.gov (NCT05254301) and has been published elsewhere 33 in accordance with the Standard Protocol Items: Recommendations for Interventional Trials (SPIRIT) guidelines. The trial was conducted in accordance with the Declaration of Helsinki. The Medical Ethics Committee of UZ Brussel/Vrije Universiteit Brussel approved the study (BUN: 1432022000068). Study design and setting: This is a pilot pragmatic, single centre, randomized controlled trial with 2 parallel groups: standard physiotherapy and the personalized multimodal therapy (PMT). The assessments and data collection were performed at Universitair Ziekenhuis Brussel , Brussels, Belgium. The physiotherapy sessions took place either in the hospital or in a private practice. The nutritional counselling took place during weekly phone or video calls. Participants were randomized using an interactive web response system within the electronic case report form CASTOR EDC ( www.castoredc.com ). They were randomized into one of the two intervention arms in a 1:1 ratio, using permuted block randomization with variable block sizes (2-4-6). A trial coordinator assigned the participants to their allocated intervention. The assessor during the study visits was blinded, participants were asked not to mention their group allocation during the study visits. Study population: Between May 2022 and September 2023, 65 participants out of 66 planned inclusions were recruited through referral from health care workers or advertisements on traditional and social media. The sample size calculation for the pilot was based on 25 participants per treatment arm in line with Whitehead et al. 34 , standardised mean difference of .2, power of .9, two-sided 5% significance and considering an attrition rate of 20%. Inclusion criteria were: Dutch, French or English-speaking. At least 18 years old. Laboratory confirmed diagnosis of COVID-19 or probable diagnosis based on clinical signs. Experienced persisting symptoms of PEM and/or fatigue and/or muscle pain lasting > 12 weeks from onset of symptoms. Enrolled in a Belgian health insurance. Exclusion criteria were: Having an alternative diagnosis for the previously mentioned symptoms. Having a known metabolic disorder (e.g. uncontrolled diabetes). Unable to undergo a rehabilitation program due to acute or unstable conditions or comorbidities. Having received more than nine physiotherapy sessions with focus on motor and/or respiratory therapy for long COVID or any COVID-19 related diagnosis in the current calendar year. If participants suffered a reinfection with SARS-CoV-2 during the trial, their participation ended. Written informed consent was obtained during the screening consultation. Experimental intervention: personalised multimodal therapy The PMT consisted of the complementary parts: nutritional counselling and physical therapy. Personalised nutritional counselling The focus of the nutritional counselling was to align energy and protein intake with individual needs. A nutritional anamnesis was performed prior to the counselling sessions, based on dietetic practice 35 . The goal was to assess the usual intake, usual eating patterns, weight evolution, risk for malnutrition, specific eating issues or issues with the absorption of nutrients (e.g., persistent symptoms like nausea, diarrhoea, loss of taste or smell). Body composition was determined using Bioelectrical Impedance Analysis ((BIA 101 BIVA® PRO AKERN srl, Florence, Italy) 36 . To define the individual energy need , the dietitian first measured each participant's Resting Energy Expenditure (REE) through indirect calorimetry (IC) in canopy dilution mode (Q-NRG™ Metabolic Monitor, COSMED) 37 . The use of IC to determine the REE in is considered the golden standard, as estimation equations are inaccurate in individual patients 37 . To determine the total energy expenditure (TEE), the measured REE was multiplied by a Physical Activity Level (PAL) (TEE = REE x PAL) 38 . The PAL was assigned in accordance with the Belgian High Health Council 39 . The factor ranges from less than 1.4 (i.e. inactive) to more than 1.8 (i.e. very active) 38 , 39 . To define individual protein need , 0.83 g per kg bodyweight was used 39 , 40 , unless a higher need was recommended by the ESPEN guidelines depending on specific health conditions (e.g. after hospitalisation, in older participants or in case of sarcopenia) 41 – 43 . The Belgian High Health Council guidelines of 50–55 energy percent (En%) from carbohydrates and ≥ 20 and ≤ 35 En% for lipids were used as guidelines for the intake of the other macronutrients 39 . Based on the body composition (high or low fat mass of fat-free mass), the dietitian decided if a caloric surplus or caloric deficit of maximally 500 kcal was necessary, and the nutritional targets were adjusted according to dietetic practice 35 . To assess the nutritional intake, the dietitians calculated the mean daily intake from 3-day food diary using the Belgian Food Composition Database NUBEL 44 . They compared the mean daily energy and protein intake with the individual needs, and the mean daily carbohydrate and lipid intake with the guidelines from the Belgian High Health Council 39 , to assess the quality of the usual intake. The energy-feeding adequacy (EFA) was calculated as the ratio between the mean energy intake and the requirement. Based on these results and the nutritional anamnesis, the dietitians gave personalised nutritional counselling, considering both the qualitative and quantitative nutritional aspects. This was done during weekly tele-consultations with the participants between baseline and the end of the intervention period (12 weeks ± 7 days). This is a low-threshold intervention with proven benefit and feasibility 45 . As this was a pragmatic trial, the dietitians were able to use any evidence-based tool that they would use in usual, personalised care. This included dietary adjustments based on meal composition, portion sizes and frequency, education on specific product choices etc. If necessary, nutritional therapy consisting of oral supplements could be prescribed after consultation with a medical doctor within the study team. Personalised physical exercise program. The exercise program followed the recommendations of the World Physiotherapy Organisation for patient-tailored physical exercise 46 . A symptom-titrated pacing strategy was implemented to account for exercise intolerance or PEM. Individuals with PEM were identified by inquiring about their symptoms and the impact of physical, cognitive, and social activities on symptoms 12 hours or longer after exertion 46 . If PEM was present, symptom stabilization was prioritized. Consequently, symptom-contingent pacing was used to guide activities based on perceived symptom levels to avoid worsening symptoms, conserve energy, and enable participation in meaningful activities. Therapists and participants focused on energy conservation and balancing activities with rest to prevent further aggravation. Progression to subsequent stages in the exercise program was based on individual measures of perceived exertion and a visual analogue scale for symptoms. Over a period of 12 weeks, participants trained a maximum of 2 to 3 times per week, with 18 sessions supervised by a trained physiotherapist. The physiotherapist's objective was to teach participants to independently plan and pace their activities of daily life and to slowly increase the training load based on individual assessments and symptoms. The program consisted of different progressive phases, including preparation for return to exercise (e.g., breathing and stretching), low-intensity activity, moderate-intensity analytical and functional exercises, and return to pre-COVID activity levels. Control intervention: standard physiotherapy. The participants of the control group received a maximum of 18 supervised sessions with a physiotherapist containing standard care. The participants received an information leaflet (following the World Physiotherapy Organisation recommendations) with information regarding symptom-contingent pacing to inform their physiotherapist, as well as general recommendations on healthy nutrition based on the recommendations of the Belgian High Health Council. Study endpoints The four study visits took place at baseline (T0), 6 weeks ± 7 days of intervention (T1), 12 weeks ± 7 days (= end of intervention) (T2) and follow-up 6 weeks ± 7 days after end of intervention (T3). The main outcomes of the pilot were recruitment feasibility, attrition rate, intervention feasibility and study burden. Intervention feasibility consisted of the adherence to the nutritional teleconsultations, calculated as the ratio of the number of teleconsultations that were carried out versus the number of planned consultations, and the number of attended physiotherapy sessions out of the 18 prescribed sessions. The study burden was assessed by using statements C4 (“Overall, I was satisfied with my trial experience”) and C5 (“Compared to when the trial started, the overall commitment required was similar to what I expected”) of the Study Participant Feedback Questionnaire (SPFQ) (TransCelerate Biopharma Inc) 47 . Based on discussions with a patient-representative, outcomes were chosen to assess the effectiveness of the PMT. To determine the necessary sample size for a powered RCT to show an effect between the PMT and standard physiotherapy, the primary effectiveness outcome was the difference in 1-minute sit-to-stand (1-MSTS) repetitions at T2. The 1-MSTS test has been used in a multitude of populations 48 – 50 , but few studies have been performed in the long COVID population 51 – 55 . At the time of the design of this pilot study, no core-outcome set had been defined, so other outcomes were included to assess the effect of the PMT. The full list of outcomes can be found in the published protocol 33 . Here we describe the findings for the 6-minute walk test (6-MWT) that was used to measure physical performance, and for the Multidimensional Fatigue Inventory (MFI-20) that was used to assess fatigue. The MFI-20 scores general fatigue, physical fatigue, reduced activities, reduced motivation, and mental fatigue, with a range between 4 and 20, a higher score indicating more fatigue 56 . The baseline mean daily intake of calories (kcal per day), proteins (g per kg per day), lipids (g and En%) and carbohydrates (g and En%) are reported and compared to the guidelines. The EFA based on the TEE (EFA TEE ) was calculated as the mean daily energy intake (kcal per day)/TEE (kcal per day). Additionally, the EFA based on the REE (EFA REE ) was calculated as the mean daily energy intake (kcal per day)/REE (kcal per day). Statistics and reproducibility: Descriptive analysis was performed using IBM SPSS (version 29.0.0.). To gain insight into the distribution of the effectiveness outcomes For each of effectiveness outcomes the mean, standard deviation (SD) and the 95% confidence interval (95% CI) were calculated for the within and between group changes between each follow-up study visit and the baseline assessment. Sample sizes were calculated using G*Power 3.1.9.2. for a large scale RCT based on the 1-MSTS, 6-MWT and physical fatigue changes after 18 weeks. We aimed for a power of .8, allowed a type II error of .05 (two-sided), and used the SD of both groups between T3 and T0 and the Pearson correlation coefficient (r) of both groups between T3 and T0 and the minimally clinically important differences (MCIDs) to define the effect sizes. For 1-MSTS, a MCID of + 3 was used 49 , for the 6-MWT a MCID of + 14 was used 57 , and for physical fatigue a MCID of -2 was used 58 . Results Baseline characteristics The mean age of the participants was 43 ± 10 years, and the majority (64.6%) were female. The mean BMI was 26 ± 4 kg per m². Most participants had a mild COVID-19 disease course (9.2% was hospitalised and 3.1% was admitted to the ICU). The mean duration of long COVID symptoms was 78 ± 43 weeks. During the 1-MSTS the participants performed 24 ± 8 sit-to-stand repetitions. During the 6-MWT the participants walked 536 ± 97 meters. The MFI-20 scores in the study population were right-skewed, indicating high fatigue, with 17 ± 4 for general fatigue, 17 ± 3 for physical fatigue, 15 ± 3 for reduced activity, 12 ± 3 for reduced motivation, and 14 ± 4 for mental fatigue. The REE was 1823 ± 365 kcal per day or 24 ± 4 kcal per kg bodyweight per day. The PAL was 1.6 ± 0.1, leading to a TEE of 2848 ± 647. The mean daily energy intake, calculated from the 3-day food diary, was 1876 ± 478. The EFA TEE was 0.69 ± 0.21, and the EFA REE was 1.06 ± 0.31. The mean daily carbohydrate intake was 203 ± 70 g per day (43 ± 7 En%). The mean daily lipid intake was 76 ± 23 g per day (36 ± 7 En%). The mean daily protein intake was 74 ± 21 g per day (1.01 ± 0.37 g per kg per day). When compared to the guidelines for nutritional needs, 48.3% had an EFA REE < 1, 42.8% had a protein intake < 0.83 g per kg body weight, 83.1% had a carbohydrate intake 35 En%. Descriptives of both groups can be found in Table 1 . Interesting findings While this pilot study was not set up to have sufficient power to show any interaction between the changing effectiveness outcomes (1-MSTS, 6-MWT and MFI-20) and our experimental groups, the following sections will highlight interesting findings that can be of importance for the calculation of the sample size of future RCTs. Table 2 shows the mean difference (MD) [95% Confidence Interval] in functional performance (1-MSTS and 6-MWT) and fatigue (MFI-20) throughout the different study visits, for each group. There was no significant difference in 1-MSTS repetitions at the primary endpoint (T2) between both groups as reflected by a non-significant MD of -0.97 [-3.70, 1.75] repetitions. However, the estimated effect between the groups increased over the trial duration, from a MD -0.65 [-2.95, 1.65] at T1 to -2.14 [-5.54, 1.26]) at T3. This is mainly due to an observed positive trend in the PMT group (see Fig. 1 ) with significant mean differences within the PMT group ranging from a MD 2.37 [0.93, 3.81]) at T1 to 5.32 [2.94, 7.70]) at T3. A similar positive trend was observed for the 6-MWT, as the estimated effect between groups increased from a MD of -5.51 [-29.1, 18.7]) at T1 to -23.99 [-59.03, 11.04]) at T3. Again, this is explained by a positive trend in the PMT group (see Fig. 2 ) with significant mean differences within the PMT group ranging from 13.65 [1.74, 25.56]) at T1 to 34.79 [15.89, 53.70] at T3. For physical fatigue, the mean difference between groups at T3 was significant, with an estimated effect of 2.21 [0.13, 4.29]). This indicates that the PMT has a beneficial effect on physical fatigue compared to standard physiotherapy. The PMT group showed a significant reduction by T3 (MD of -2.12 [-3.84, -0.40]), which was not seen in the control group (MD of 0.09 [-1.18, 1.36]). For general fatigue, reduced activity, reduced motivation, and mental fatigue no significant changes were observed within either group across all study visits. No significant between-group difference was observed. However, a growing effect within the PMT group was observed (see Fig. 3 ), which was near significance for general fatigue (MD of -1.28 [-2.59, 0.03]), reduced activity (MD of-1.48 [-2.96, 0.00]) and mental fatigue (MD of -1.44 [-2.93, 0.05]) at T3. Table 1 Baseline characteristics Total sample (n = 65) Control group (n = 33) PMT group (n = 32) Population characteristics Sex (% female) 64.6 63.6 65.6 Age (years) (mean ± SD) 43 ± 10 44 ± 11 43 ± 11 Smoking (% yes) 4.6 9.1 0.0 Hospitalised during COVID-19 (% yes) 9.2 9.1 9.4 Length of hospitalisation (mean ± SD) 16 ± 18 19 ± 24 13 ± 15 Admitted to ICU (% yes) 3.1 3.0 3.1 Length of ICU admission (days) (mean ± SD) 20 ± 16 31 ± 0 9 ± 0 Long COVID duration (weeks) (mean ± SD) 78 ± 43 81 ± 44 75 ± 42 Body Mass Index (kg/m²)(mean ± SD) 26 ± 4 26 ± 4 25 ± 4 Functional performance 1-MSTS repetitions (mean ± SD) 24 ± 8 24 ± 10 24 ± 6 6-MWT (meters)(mean ± SD) 536 ± 97 531 ± 114 542 ± 76 Fatigue General fatigue (mean ± SD) 17 ± 4 16 ± 4 17 ± 3 Physical fatigue (mean ± SD) 17 ± 3 17 ± 3 17 ± 3 Reduced activity (mean ± SD) 15 ± 3 14 ± 3 16 ± 3 Reduced motivation (mean ± SD) 12 ± 3 12 ± 3 12 ± 3 Mental fatigue (mean ± SD) 14 ± 4 15 ± 4 14 ± 4 Nutritional parameters REE kcal/day (mean ± SD) 1823 ± 365 1802 ± 364 1845 ± 370 kcal/kg/day (mean ± SD) 24 ± 4 24 ± 3 24 ± 4 PAL (mean ± SD) 1.6 ± 0.1 1.6 ± 0.1 1.6 ± 0.1 TEE (mean ± SD) 2848 ± 647 2812 ± 704 2888 ± 588 Energy intake (kcal/day) (mean ± SD) 1876 ± 478 1860 ± 483 1892 ± 479 EFA TEE 0.69 ± 0.21 0.69 ± 0.22 0.68 ± 0.2 EFA REE 1.06 ± 0.31 1.07 ± 0.31 1.05 ± 0.32 Carbohydrate intake g/day (mean ± SD) 203 ± 70 206 ± 68 200 ± 74 En% (mean ± SD) 43 ± 7 44 ± 5 42 ± 8 Lipid intake g/day (mean ± SD) 76 ± 23 74 ± 22 78 ± 23 En% (mean ± SD) 36 ± 7 36 ± 6 37 ± 7 Protein intake g/day (mean ± SD) 74 ± 21 72 ± 21 75 ± 21 g/kg/day (mean ± SD) 1.01 ± 0.37 0.99 ± 0.33 1.03 ± 0.4 Values are shown as mean (standard error (SD)) or % yes. 1-MSTS: one-minute sit-to-stand; 6-MWT: six-minute walk test; EFA REE : energy-feeding adequacy based on the Resting Energy Expenditure (REE); EFA TEE : energy-feeding adequacy based on the Total Energy Expenditure (TEE); En%: energy percent; PAL: physical activity level; PMT: personalized multimodal treatment. Table 2 Mean changes in functional performance and fatigue Control group PMT group Mean difference n mean [95% CI] n mean [95% CI] mean [95% CI] 1-MSTS Change between T1 and T0 25 1.72 [-0.14, 3.58] 27 2.37 [0.93, 3.81] -0.65 [-2.95, 1.65] Change between T2 and T0 22 2.55 [0.27, 4.82] 27 3.52 [1.9, 5.14] -0.97 [-3.7, 1.75] Change between T3 and T0 22 3.18 [0.62, 5.74] 25 5.32 [2.94, 7.70] -2.14 [-5.54, 1.26] 6-MWT Change between T1 and T0 25 8.14[ -12.74, 29.02] 26 13.65 [1.74, 25.56] -5.51 [-29.1, 18.07] Change between T2 and T0 22 3.75[ -25.56, 33.06] 27 21.26 [5.13, 37.39] -17.51 [-50.31, 15.29] Change between T3 and T0 22 10.8[ -19.67, 41.26] 24 34.79 [15.89, 53.70] -23.99 [-59.03, 11.04] General fatigue Change between T1 and T0 26 -0.31 [-1.68, 1.06] 29 -0.14 [-1.69, 1.42] -0.17 [-2.19, 1.85] Change between T2 and T0 22 -0.64 [-3.17, 1.90] 27 -0.22 [-1.4, 0.95] -0.42 [-3.16, 2.34] Change between T3 and T0 22 0.18 [-2.36, 2.72] 25 -1.28 [-2.59, 0.03] 1.46 [-1.34, 4.27] Physical fatigue Change between T1 and T0 25 -0.52 [-1.71, 0.67] 29 -0.83 [-2.48, 0.83] 0.31 [-1.69, 2.30] Change between T2 and T0 22 -0.27 [-1.66, 1.12] 27 -0.78 [-1.91, 0.36] 0.51 [-1.24, 2.25] Change between T3 and T0 22 0.09 [-1.18, 1.36] 25 -2.12 [-3.84, -0.40] 2.21 [0.13, 4.29] Reduced activity Change between T1 and T0 25 0.92 [-0.32, 2.16] 29 -0.34 [-1.48, 0.79] 1.26 [-0.38, 2.91] Change between T2 and T0 22 -0.32 [-1.47, 0.84] 27 -0.15 [-1.59, 1.29] -0.17 [-1.97, 1.63] Change between T3 and T0 22 -0.45 [-1.77, 0.86] 25 -1.48 [-2.96, 0.00] 1.03 [-0.91, 2.96] Reduced motivation Change between T1 and T0 25 0.36 [-1.62, 2.34] 29 0.62 [-0.50, 1.75] -0.26 [-2.50, 1.98] Change between T2 and T0 22 -0.09 [-2.08, 1.90] 27 -0.48 [-1.77, 0.81] 0.39 [-1.93, 2.71] Change between T3 and T0 22 0.41 [-1.61, 2.43] 25 -0.76 [-2.03, 0.51] 1.17 [-1.16, 3.5] Mental fatigue Change between T1 and T0 25 -0.44 [-1.93, 1.05] 29 0.31 [-0.93, 1.55] -0.75 [-2.64, 1.14] Change between T2 and T0 22 -0.05 [-2.05, 1.96] 27 0.19 [-1.1, 1.47] -0.24 [-2.56, 2.1] Change between T3 and T0 22 0.14 [-1.73, 2.00] 25 -1.44 [-2.93, 0.05] 1.58 [-0.75, 3.9] Values are shown as mean [95% Confidence Interval]. 1-MSTS: one-minute sit-to-stand; 6-MWT: six-minute walk test. Feasibility In total, 141 individuals were assessed for eligibility of which 65 were included (see Fig. 5 ). Recruitment took 16 months (average 9 per month). The attrition was 18.5% at T1, 24.6% at T2 and 27.7% at T3. The study and the PMT was considered comparable to that of standard of care. One medically significant event was reported (one participant was admitted to the emergency care), but no causality between the study intervention was suspected. Participants in the PMT group had 10 ± 4 teleconsultations with the dietitian (range: 0–13). Average adherence to the nutritional counselling sessions was 0.83 ± 0.28. However, in the participants who had an early trial termination, the adherence was 0.45 ± 0.39. Participants received 14 ± 4 and 13 ± 5 physiotherapy sessions in the PMT and control group respectively during the interventional period. Additionally, 77.1% of participants who completed the trial indicated that they continued the intervention after T2. Figure 4 shows the participant study burden results. Sample size calculations As discussed in a previous section, the estimated effect between groups increased over the trial duration for the 1-MSTS, 6-MWT and MFI-20. This indicates that extending the intervention period from 12 weeks to 18 weeks is more beneficial. Based on these results, the SD and r for all effectiveness outcomes were calculated for the mean change between T3 and T0 (1-MSTS: SD = 8.18, r = 0.78; 6-MWT: SD = 92.2, r = 0.82; physical fatigue: SD: 3.05, r = 0.53). Using these parameters and the observed data distribution from this pilot study, the required sample sizes to achieve the minimally clinically important difference (MCID) between the PMT group and the control group are estimated to be 32 participants for the 1-MSTS, 142 Participants for the 6-MWT, and 29 participants for the physical fatigue measure. Taking into account the attrition rate of 27.7% at T3, a total sample size of 181 participants should be recruited for RCT. Discussion We hypothesised that a personalised multimodal treatment (PMT), consisting of personalised nutritional counselling and physiotherapy would provide a synergistic effect, offering a comprehensive strategy to manage fatigue and improve the physical performance of individuals with long COVID. This pilot pragmatic randomized controlled trial examined the feasibility of the PMT, as well as the effectiveness compared to standard physiotherapy alone. Positive effects were seen on physical performance outcome parameters, the 1-MSTS and the 6-MWT (see Table 1 and Figs. 1 – 2 ). The mean results in the study population at baseline were low compared to reference values in healthy adults 59 , 60 , but were similar to those found in other post-COVID studies 51 – 55 . Although we did not find a significant effect for the performance outcomes between the intervention groups, both 1-MSTS and 6-MWT improved within the PMT group, while the improvement was not seen in the control group. For the 1-MSTS, the Minimal Clinically Important Difference (MCID) of + 3 repetitions based on the Chronic Obstructive Pulmonary Disease (COPD) population 49 was reached after 12 weeks and continued to improve. For the 6-MWT, the smallest MCID of 14 meters 57 was nearly reached in the PMT after 6 weeks, while it was not reached in the control group, even after 18 weeks. Zheng et al. also showed these positive effects of physical rehabilitation intervention on exercise capacity (effect size estimate for 6-MWT of 94.76 (14.83 to 174.70) and 1-MSTS of 0.54 (-0.13 to 1.22) and fatigue (effect size estimate 0.57 (0.15 to 0.98) [32]. However, the evidence remains uncertain because of low quality studies with high risk of bias 31 , 32 , 61 . A possible reason could be the heterogenicity of the physical rehabilitation interventions: breathing exercises either alone or in combination with resistance and/or aerobic training, only aerobic training or in combination with strengthening, stretching, motor or balance training etc. Interventions were all compared with usual care in the form of respiratory training and exercises-based, self-management education. This is a big difference with our study were the control group received supervised physiotherapy sessions with some additional advice such as breathing exercises and pacing, and the PMT group received the additional nutritional counselling to support the physical rehabilitation. One of the foundational principles of this study is the concept of combined nutrition and physiotherapy in the context of long COVID management. Exercise and nutrition plans were tailored based on each patient's specific individual symptoms and nutritional adequacy, respectively. This approach aligns with the growing recognition that long COVID presents with a highly variable symptomatology 6 – 10 , necessitating customized treatment plans. By evaluating individual metabolic rates and dietary preferences, the personalized program aimed to optimize energy levels and promote muscle recovery more effectively than standard physiotherapy alone. Traditional physiotherapy does not typically integrate dietary management, potentially overlooking an essential aspect of recovery. Our study is the first to report the results of a multidisciplinary rehabilitation program including both nutritional and physical rehabilitation in individuals with a longer duration of long COVID, and with a variety of COVID-19 disease history, of which the majority was not hospitalized. The positive effect of nutritional intervention was also found by Gobbi et al. who performed a 28-day long multidisciplinary intervention including nutritional therapy based on the ESPEN guidelines in post-acute COVID-19 patients after discharge 62 . This highlights the need for a comprehensive nutritional intervention in the post-acute phase of the recovery 62 . Dietary interventions in the long COVID population generally focus on nutritional supplements, even when nutrition is proposed as part of a multidisciplinary approach 63 – 69 . The evidence from these studies is insufficient to propose specific nutritional supplements as treatments for long COVID. Even in similar conditions to long COVID, such as Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) or fibromyalgia, dietary interventions usually consist of nutritional supplements 70 , 71 . While there are no specific long COVID-dietary guidelines, the recommendations for energy, macronutrient and micronutrient intake in individuals recovering from a SARS-CoV-2 infection fit within evidence-based dietetic practice 43 , 72 . By opting for counselling by a dietitian, individuals learn how to adhere to the nutritional recommendations whilst making changes that are compatible with their long COVID symptoms. Personalized nutrition is an evidence-based approach that uses additional individual data (such as anthropometric, biochemical, metabolic data), to tailor general population-based interventions to each patient 73 . The complexity of personalization may cause difficulty in the reproducibility of study results. However, especially in long COVID, a one-size-fits-all approach is insufficient, due to the heterogeneity of the population 5 . A strength of this study is the involvement of a patient representative during the conceptualisation of the protocol and as a committee member throughout the study. Another notable strength of our study is the use of indirect calorimetry (IC) to measure REE for personalized nutritional counselling in long COVID patients, offering a more accurate determination of energy requirements compared to predictive equations, which can overestimate REE by more than 900 kcal per day 74 . Previous studies have applied this method to hospitalized and critically ill COVID-19 patients during hospitalization 75 – 79 , and to non-hospitalized COVID-19 patients before and after the acute SARS-CoV-2 infection 74 . However, to our knowledge, our study is the first to report the use of IC to determine the energy requirements of individuals with long COVID. A limitation of using indirect calorimetry in mobile individuals is that their daily energy requirements are not solely based on their REE, as in bedridden or critically ill patients, but also depend significantly on the energy expenditure during their daily physical activities. Therefore, we adhered to guidelines to estimate the TEE by multiplying the REE with a physical activity factor 38 , 39 . However, a limitation arises from the potential overestimation of Physical Activity Level (PAL) values, affecting the calculation of Total Energy Expenditure (TEE). In this study, the EFA TEE was 0.69, indicating that the participants generally had caloric deficit of almost 30%. Based on the nutritional assessments by the dietitians (e.g. weight evolution, nutritional anamnesis), the study team concluded that the PAL values recommended by the Belgian High Health council may not accurately reflect the energy expenditure of mobile individuals. Despite the potential overestimation of PAL, the results still indicate a low energy feeding adequacy when comparing mean daily energy intake with measured daily REE. At baseline, almost half of the participants (48.3%) had an EFA REE < 1, meaning that their nutritional intake did not cover the resting energy expenditure, let alone any additional physical activity. Additionally, 42.8% consumed less proteins that the minimally recommended dose of 0.83g per kg body weight. Most participants consumed less carbohydrates and more lipids than recommended by the High Health Council. We can conclude that the nutritional intake of a significant part of the study population at baseline was disbalanced in macronutrient intake and the total energy intake was insufficient. While using nutritional diaries to calculate daily intake is susceptible to various biases—such as social desirability bias (e.g., underreporting foods perceived as “unhealthy” or overreporting foods perceived as “healthy”), inaccurate estimations of portion sizes, and omissions of ingredients—the findings still highlight significant gaps in meeting energy requirements. The results from this study confirm that nutritional optimization is a potential target for the management of long COVID symptoms and emphasize the need for nutritional counselling by a registered dietitian as part of a multidisciplinary team. Future research should utilize more precise methods, such as accelerometer devices 80 in combination with indirect calorimetry, to measure physical activity energy expenditure and determine daily TEE more accurately. Additionally, longitudinal studies that examine the changes in PAL and TEE over time in long COVID patients could enhance the accuracy of energy requirement estimations. Overall, the intervention was found feasible. Future studies with this intervention should consider a higher attrition, depending on the length of the intervention (almost 25% after 12 weeks, almost 28% after 18 weeks). Based on the data gathered in this study, the (expected) study burden was an important limiting factor in both recruitment and attrition (see Fig. 1 ). On the other hand, participants who completed the trial indicated that although the study burden was high, they were satisfied with their trial experience (see Fig. 2 ). Additionally, the intervention-specific procedures, i.e. the teleconsultations with the dietitian and the physiotherapy sessions, were considered feasible. The data from this pilot can help address the concern for the study burden, which could potentially facilitate the recruitment of participants for a larger scale RCT. While this pilot study was not set up to have sufficient power to show any interaction between the changing effectiveness outcomes (1-MSTS, 6-MWT and MFI-20) and our experimental groups, a visualization does reveal very promising results (see Figs. 1 to 3 ). The individual evolutions themselves show a consistent pattern, which would help to uncover treatment effects in future studies. Some patients nevertheless show very different patterns, and with additional data in a larger scale RCT it will be possible to further focus on how patients differ in their evolution. Generally, the study revealed a positive trend for improved physical performance and reduced fatigue in the PMT group, that was not observed in the control group, with benefits especially persisting after the program's conclusion at 12 weeks. This indicates that a longer interventional period of at least 18 weeks is preferable. These are hopeful results, as the combined positive effect of reduced fatigue, combined with an increased physical performance after the PMT could be a therapeutic target to help manage long COVID symptoms like fatigue and PEM. To demonstrate these promising results, an RCT is needed with a sample size of 181 participants. Declarations Acknowledgements: The Belgian Healthcare Knowledge Centre (KCE) funded this study under the KCE Trials Long COVID call (LCOV-211306). We like to thank Mme Ann Li, chair of the “ post-COVID gemeenschap ” for her advice as patient representative of this trial. We like to thank Dr. Marc Schiltz, Ann De Smet, Koen Putman, Joy Demol and Janne Geers for their contribution to the conceptualisation of the original protocol. They have been credited authorship in the published protocol. Autor contributions : Conceptualisation: B.G.J.G., S.R., L.L., D.B. and E.D.W. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-4914245","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Article","associatedPublications":[],"authors":[{"id":375379258,"identity":"8c9482fd-39fb-47a0-80ab-4ae171a8ea5b","order_by":0,"name":"Berenice Jimenez Garcia","email":"data:image/png;base64,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","orcid":"https://orcid.org/0000-0002-3277-5682","institution":"Vrije Universiteit Brussel (VUB), Universitair Ziekenhuis Brussel (UZ Brussel)","correspondingAuthor":true,"prefix":"","firstName":"Berenice","middleName":"Jimenez","lastName":"Garcia","suffix":""},{"id":375379259,"identity":"c0f9ee7d-8122-4280-82ec-369625fc5f43","order_by":1,"name":"Stijn Roggeman","email":"","orcid":"","institution":"","correspondingAuthor":false,"prefix":"","firstName":"Stijn","middleName":"","lastName":"Roggeman","suffix":""},{"id":375379260,"identity":"f7a938e1-bbc4-461e-8bb9-58d54e101953","order_by":2,"name":"Lynn Leemans","email":"","orcid":"","institution":"","correspondingAuthor":false,"prefix":"","firstName":"Lynn","middleName":"","lastName":"Leemans","suffix":""},{"id":375379261,"identity":"c8c51b60-37ab-42f6-9c49-3d136bcf9134","order_by":3,"name":"Wilfried Cools","email":"","orcid":"","institution":"","correspondingAuthor":false,"prefix":"","firstName":"Wilfried","middleName":"","lastName":"Cools","suffix":""},{"id":375379262,"identity":"200ec282-db6c-4d20-98ad-e696b17eab72","order_by":4,"name":"David Beckwée","email":"","orcid":"","institution":"","correspondingAuthor":false,"prefix":"","firstName":"David","middleName":"","lastName":"Beckwée","suffix":""},{"id":375379263,"identity":"50ca902d-7fea-4b4d-ae21-3065102954f8","order_by":5,"name":"Elisabeth De Waele","email":"","orcid":"","institution":"Vrije Universiteit Brussel (VUB), Universitair Ziekenhuis Brussel (UZ Brussel)","correspondingAuthor":false,"prefix":"","firstName":"Elisabeth","middleName":"","lastName":"De Waele","suffix":""}],"badges":[],"createdAt":"2024-08-14 14:10:31","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-4914245/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-4914245/v1","draftVersion":[],"editorialEvents":[{"content":"https://doi.org/10.1038/s43856-026-01486-w","type":"published","date":"2026-03-03T05:00:00+00:00"}],"editorialNote":"","failedWorkflow":false,"files":[{"id":71002786,"identity":"c44d03e4-9d34-4619-ac9a-bb3b75a141b4","added_by":"auto","created_at":"2024-12-10 06:00:25","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":1337712,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eEvolution of the 1-MSTS results throughout the trial. \u003c/strong\u003eThe graph shows the evolution in functional performance assessed by the one-minute sit-to-stand (1-MSTS) test, for the individual participants (dotted line), as well as the mean evolution (full line) for both groups. The difference between the PMT group and the control group becomes more visible towards the end of the trial, indicating a positive trend for the use of the PMT for a longer interventional period.\u003c/p\u003e","description":"","filename":"Figure1.png","url":"https://assets-eu.researchsquare.com/files/rs-4914245/v1/74aeafcc7e1ca67e7fbea30d.png"},{"id":71002783,"identity":"aa9540fa-b4b0-4987-9b17-a60dd8b4e995","added_by":"auto","created_at":"2024-12-10 06:00:25","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":1366123,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eEvolution of the 6-MWT results throughout the trial\u003c/strong\u003e. The graph shows the evolution in functional performance assessed by the six-minute walk test (6-MWT), for the individual participants (dotted line), as well as the mean evolution (full line) for both groups.\u003c/p\u003e","description":"","filename":"Figure2.png","url":"https://assets-eu.researchsquare.com/files/rs-4914245/v1/9ba58369d36dc44facda1792.png"},{"id":71002785,"identity":"4b3b7f1f-7876-45e2-ab16-721760236098","added_by":"auto","created_at":"2024-12-10 06:00:25","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":6475815,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eEvolution of the MFI-20 results throughout the trial. \u003c/strong\u003eThe graph shows the evolution in the different fatigue subscales (general fatigue, physical fatigue, reduced activity, reduced motivation and mental fatigue), for the individual participants (dotted line), as well as the mean evolution (full line) for both groups.\u003c/p\u003e","description":"","filename":"Figure3.png","url":"https://assets-eu.researchsquare.com/files/rs-4914245/v1/93fc207629308e80ccfbe7db.png"},{"id":71002784,"identity":"3aea7617-1447-415e-a994-7715935f306f","added_by":"auto","created_at":"2024-12-10 06:00:25","extension":"png","order_by":4,"title":"Figure 4","display":"","copyAsset":false,"role":"figure","size":720565,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eStudy burden results. \u003c/strong\u003eThe figure shows the results of statements C4 and C5 of the Study Participant Feedback Questionnaire in the control group (n = 19) and in the PMT group (n = 25). The majority of participant was satisfied with their trial experience although a significant proportion found the overall required commitment higher than expected.\u003c/p\u003e","description":"","filename":"Figure4.png","url":"https://assets-eu.researchsquare.com/files/rs-4914245/v1/4c534fe3a0ccb003db60c439.png"},{"id":71002788,"identity":"2beb482f-b7b3-4472-97f3-0e0fe58c77dd","added_by":"auto","created_at":"2024-12-10 06:00:25","extension":"png","order_by":5,"title":"Figure 5","display":"","copyAsset":false,"role":"figure","size":17460813,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003ethe trial CONSORT Diagram\u003c/strong\u003e.\u003c/p\u003e","description":"","filename":"Figure5.png","url":"https://assets-eu.researchsquare.com/files/rs-4914245/v1/f21d1a5d005c0d6647534b9b.png"},{"id":106853946,"identity":"87a2fcb1-c5db-467e-960d-9cbae16ce24b","added_by":"auto","created_at":"2026-04-14 07:06:35","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":27750295,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-4914245/v1/50f8c856-cfd2-42af-989d-a5a0ca968685.pdf"}],"financialInterests":"There is \u003cb\u003eNO\u003c/b\u003e Competing Interest.","formattedTitle":"Increased physical performance and reduced fatigue after personalised physiotherapy and nutritional counselling in long COVID","fulltext":[{"header":"Plain language summary","content":"\u003cp\u003eFatigue and difficulty recovering from exercise can be present 12 weeks after COVID-19 without additional illness. It is not clear how to improve these symptoms. We tested, in one group, if adjusting the participants\u0026apos; diet based on measurements and food diary analysis, combined with physiotherapy could help relieve these symptoms. A second group received standard physiotherapy. The study found that those who received both nutritional counselling and physiotherapy could walk further, perform more sit-to-stand repetitions, and were less tired after 18 weeks, while the standard physiotherapy group did not improve as much. These results suggest that dietitians and physiotherapists can adjust their approach. A larger study is needed to confirm the benefits of this approach.\u003c/p\u003e\n"},{"header":"Introduction","content":"\u003cp\u003eThe Severe Acute Respiratory Syndrome Coronavirus (SARS-CoV-2) has led to over 775\u0026nbsp;million reported coronavirus disease 2019 (COVID-19) cases as of mid-August 2024\u003csup\u003e1\u003c/sup\u003e. Many COVID-19 survivors experience post-acute and long-term health effects, referred to as post-COVID-19 condition or \u0026ldquo;long COVID\u0026rdquo;, as defined by the World Health Organisation (WHO)\u003csup\u003e\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e\u003c/sup\u003e. A recent review estimates a cumulative global incidence of long COVID of over 400\u0026nbsp;million individuals\u003csup\u003e\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e\u003c/sup\u003e. Most diagnoses are seen in individuals aging 36\u0026ndash;50 years and non-hospitalised patients with a mild acute illness\u003csup\u003e\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e,\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e\u003c/sup\u003e. The symptoms associated with long COVID are diverse and include general symptoms (e.g., fatigue, post-exertional malaise (PEM), and cognitive difficulties), as well as specific symptoms affecting respiratory, cardiovascular, musculoskeletal, neurological and digestive systems\u003csup\u003e\u003cspan additionalcitationids=\"CR7 CR8 CR9\" citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e\u003c/sup\u003e. To date, there are no effective treatments. As long COVID is a multisystemic disease, the WHO guideline on the clinical management of COVID-19 emphasizes the need for multidisciplinary rehabilitation\u003csup\u003e\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e\u003c/sup\u003e. However, the effectiveness of comprehensive rehabilitation for long COVID has yet to be confirmed through randomized controlled trials (RCT)\u003csup\u003e\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003eNutrition plays a role in the prevention and management of obesity and type 2 diabetes, which are risk factors for COVID-19\u003csup\u003e13\u0026ndash;16\u003c/sup\u003e. During the acute phase of COVID-19, symptoms such as nausea, diarrhoea, anorexia, anosmia and ageusia lead to a reduced nutritional intake\u003csup\u003e\u003cspan additionalcitationids=\"CR18\" citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e\u003c/sup\u003e. Combined with the increased nutritional need caused by fever or critical illness, this leads to an increased risk of malnutrition and loss of muscle mass\u003csup\u003e\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e,\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e\u003c/sup\u003e. In long COVID, gastro-intestinal symptoms include loss of appetite, nausea and vomiting, abdominal pain, diarrhoea, constipation, heartburn, dysphagia, gastroparesis, altered bowel mobility and irritable bowel syndrome\u003csup\u003e\u003cspan additionalcitationids=\"CR22\" citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e\u003c/sup\u003e. Symptoms like fatigue and PEM lead to reduced physical activity\u003csup\u003e\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e\u003c/sup\u003e, increasing the risk for negative body composition changes, such as increase of body weight and fat mass, and loss of muscle mass\u003csup\u003e\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e\u003c/sup\u003e. Long COVID is also linked with the new onset of comorbidities such as dyslipidaemia, insulin resistance or diabetes, hypertension, and kidney or liver issues\u003csup\u003e\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e,\u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e\u003c/sup\u003e. Lifestyle interventions, including nutritional counselling, are part of the management of these conditions. Nutritional interventions address deficiencies and support metabolic processes, potentially improving energy levels\u003csup\u003e\u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e,\u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e\u003c/sup\u003e, which can be of interest for the management of fatigue or PEM. Moreover, a patient-centred approach by a registered dietitian can address personal factors that influence the nutritional intake, such as food preferences, financial factors, self-image, disordered eating, and eating behaviours (such as preparation, portions etc.). Current nutritional research in the long COVID population is of low evidence\u003csup\u003e\u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e\u003c/sup\u003e. Additionally, most studied nutritional interventions are only performed in previously hospitalized or critically ill COVID-19 patients, and these studies usually focus on nutritional supplements\u003csup\u003e\u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e\u003c/sup\u003e. Evidence is lacking for patient-centred nutritional counselling, with targeted caloric and macronutrient goals, as part of a multidisciplinary rehabilitation\u003csup\u003e\u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003ePhysical exercise enhances functioning and reduces fatigue in other conditions\u003csup\u003e\u003cspan citationid=\"CR31\" class=\"CitationRef\"\u003e31\u003c/span\u003e\u003c/sup\u003e. Systematic reviews and meta-analyses show that physical rehabilitation interventions are potential therapeutic strategies and can be applied as routine clinical practice\u003csup\u003e\u003cspan citationid=\"CR31\" class=\"CitationRef\"\u003e31\u003c/span\u003e,\u003cspan citationid=\"CR32\" class=\"CitationRef\"\u003e32\u003c/span\u003e\u003c/sup\u003e. However, given the multisystem factor and the variability in symptoms, not all patients will benefit the same on given therapy. For example, for individuals suffering from PEM physical exercise is considered harmful in some cases\u003csup\u003e\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e\u003c/sup\u003e. Therefore, personalised therapy is necessary. This highlights the need for further research, particularly to investigate additional treatments that could leverage and enhance the beneficial effects of physical exercises.\u003c/p\u003e \u003cp\u003eOur hypothesis is that nutritional counselling and physiotherapy provide a synergistic effect, offering a strategy to alleviate long COVID symptoms. This is the first study to combine comprehensive personalised nutrition and physiotherapy in adult individuals with long COVID. Due to the lack of research on such a personalised multimodal therapy (PMT) in the long COVID population, we performed a pilot study to prepare for a large-scale RCT. The goal of this pilot was to assess the feasibility of the PMT and to gain a better understanding of the effectiveness of the PMT compared to standard physiotherapy alone. We observed an advancement in both groups, however, the PMT group clearly showed a significant improvement, for 1-MST, 6-MWT and physical fatigue at 18 weeks. Participant specific trajectories suggest a growing estimated difference between groups throughout the trial. Generally, the study was found feasible. To show a minimally clinically important difference in a large-scale RCT, 181 participants should be recruited.\u003c/p\u003e"},{"header":"Methods","content":"\u003cp\u003eThe study protocol is registered at ClinicalTrials.gov (NCT05254301) and has been published elsewhere\u003csup\u003e\u003cspan citationid=\"CR33\" class=\"CitationRef\"\u003e33\u003c/span\u003e\u003c/sup\u003e in accordance with the Standard Protocol Items: Recommendations for Interventional Trials (SPIRIT) guidelines. The trial was conducted in accordance with the Declaration of Helsinki. The Medical Ethics Committee of UZ Brussel/Vrije Universiteit Brussel approved the study (BUN: 1432022000068).\u003c/p\u003e \u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003eStudy design and setting:\u003c/h2\u003e \u003cp\u003eThis is a pilot pragmatic, single centre, randomized controlled trial with 2 parallel groups: standard physiotherapy and the personalized multimodal therapy (PMT). The assessments and data collection were performed at \u003cem\u003eUniversitair Ziekenhuis Brussel\u003c/em\u003e, Brussels, Belgium. The physiotherapy sessions took place either in the hospital or in a private practice. The nutritional counselling took place during weekly phone or video calls. Participants were randomized using an interactive web response system within the electronic case report form CASTOR EDC (\u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e\u003ca href=\"https://orcid.org/0000-0002-3277-5682\" target=\"_blank\"\u003ewww.castoredc.com\u003c/a\u003e\u003c/span\u003e\u003cspan address=\"http://www.castoredc.com\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e). They were randomized into one of the two intervention arms in a 1:1 ratio, using permuted block randomization with variable block sizes (2-4-6). A trial coordinator assigned the participants to their allocated intervention. The assessor during the study visits was blinded, participants were asked not to mention their group allocation during the study visits.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec4\" class=\"Section2\"\u003e \u003ch2\u003eStudy population:\u003c/h2\u003e \u003cp\u003eBetween May 2022 and September 2023, 65 participants out of 66 planned inclusions were recruited through referral from health care workers or advertisements on traditional and social media. The sample size calculation for the pilot was based on 25 participants per treatment arm in line with Whitehead et al.\u003csup\u003e\u003cspan citationid=\"CR34\" class=\"CitationRef\"\u003e34\u003c/span\u003e\u003c/sup\u003e, standardised mean difference of .2, power of .9, two-sided 5% significance and considering an attrition rate of 20%.\u003c/p\u003e \u003cp\u003eInclusion criteria were:\u003c/p\u003e \u003cp\u003e \u003col\u003e \u003cspan\u003e \u003cli\u003e \u003cp\u003eDutch, French or English-speaking.\u003c/p\u003e \u003c/li\u003e \u003c/span\u003e \u003cspan\u003e \u003cli\u003e \u003cp\u003eAt least 18 years old.\u003c/p\u003e \u003c/li\u003e \u003c/span\u003e \u003cspan\u003e \u003cli\u003e \u003cp\u003eLaboratory confirmed diagnosis of COVID-19 or probable diagnosis based on clinical signs.\u003c/p\u003e \u003c/li\u003e \u003c/span\u003e \u003cspan\u003e \u003cli\u003e \u003cp\u003eExperienced persisting symptoms of PEM and/or fatigue and/or muscle pain lasting\u0026thinsp;\u0026gt;\u0026thinsp;12 weeks from onset of symptoms.\u003c/p\u003e \u003c/li\u003e \u003c/span\u003e \u003cspan\u003e \u003cli\u003e \u003cp\u003eEnrolled in a Belgian health insurance.\u003c/p\u003e \u003c/li\u003e \u003c/span\u003e \u003c/ol\u003e \u003c/p\u003e \u003cp\u003eExclusion criteria were:\u003c/p\u003e \u003cp\u003e \u003col\u003e \u003cspan\u003e \u003cli\u003e \u003cp\u003eHaving an alternative diagnosis for the previously mentioned symptoms.\u003c/p\u003e \u003c/li\u003e \u003c/span\u003e \u003cspan\u003e \u003cli\u003e \u003cp\u003eHaving a known metabolic disorder (e.g. uncontrolled diabetes).\u003c/p\u003e \u003c/li\u003e \u003c/span\u003e \u003cspan\u003e \u003cli\u003e \u003cp\u003eUnable to undergo a rehabilitation program due to acute or unstable conditions or comorbidities.\u003c/p\u003e \u003c/li\u003e \u003c/span\u003e \u003cspan\u003e \u003cli\u003e \u003cp\u003eHaving received more than nine physiotherapy sessions with focus on motor and/or respiratory therapy for long COVID or any COVID-19 related diagnosis in the current calendar year.\u003c/p\u003e \u003c/li\u003e \u003c/span\u003e \u003c/ol\u003e \u003c/p\u003e \u003cp\u003eIf participants suffered a reinfection with SARS-CoV-2 during the trial, their participation ended. Written informed consent was obtained during the screening consultation.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec5\" class=\"Section2\"\u003e \u003ch2\u003eExperimental intervention: personalised multimodal therapy\u003c/h2\u003e \u003cp\u003eThe PMT consisted of the complementary parts: nutritional counselling and physical therapy.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec6\" class=\"Section2\"\u003e \u003ch2\u003ePersonalised nutritional counselling\u003c/h2\u003e \u003cp\u003eThe focus of the nutritional counselling was to align energy and protein intake with individual needs. A nutritional anamnesis was performed prior to the counselling sessions, based on dietetic practice\u003csup\u003e\u003cspan citationid=\"CR35\" class=\"CitationRef\"\u003e35\u003c/span\u003e\u003c/sup\u003e. The goal was to assess the usual intake, usual eating patterns, weight evolution, risk for malnutrition, specific eating issues or issues with the absorption of nutrients (e.g., persistent symptoms like nausea, diarrhoea, loss of taste or smell). Body composition was determined using Bioelectrical Impedance Analysis ((BIA 101 BIVA\u0026reg; PRO AKERN srl, Florence, Italy)\u003csup\u003e\u003cspan citationid=\"CR36\" class=\"CitationRef\"\u003e36\u003c/span\u003e\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003eTo define \u003cem\u003ethe individual energy need\u003c/em\u003e, the dietitian first measured each participant's Resting Energy Expenditure (REE) through indirect calorimetry (IC) in canopy dilution mode (Q-NRG\u0026trade; Metabolic Monitor, COSMED)\u003csup\u003e\u003cspan citationid=\"CR37\" class=\"CitationRef\"\u003e37\u003c/span\u003e\u003c/sup\u003e. The use of IC to determine the REE in is considered the golden standard, as estimation equations are inaccurate in individual patients\u003csup\u003e\u003cspan citationid=\"CR37\" class=\"CitationRef\"\u003e37\u003c/span\u003e\u003c/sup\u003e. To determine the total energy expenditure (TEE), the measured REE was multiplied by a Physical Activity Level (PAL) (TEE\u0026thinsp;=\u0026thinsp;REE x PAL)\u003csup\u003e\u003cspan citationid=\"CR38\" class=\"CitationRef\"\u003e38\u003c/span\u003e\u003c/sup\u003e. The PAL was assigned in accordance with the Belgian High Health Council\u003csup\u003e\u003cspan citationid=\"CR39\" class=\"CitationRef\"\u003e39\u003c/span\u003e\u003c/sup\u003e. The factor ranges from less than 1.4 (i.e. inactive) to more than 1.8 (i.e. very active)\u003csup\u003e\u003cspan citationid=\"CR38\" class=\"CitationRef\"\u003e38\u003c/span\u003e,\u003cspan citationid=\"CR39\" class=\"CitationRef\"\u003e39\u003c/span\u003e\u003c/sup\u003e. To define \u003cem\u003eindividual protein need\u003c/em\u003e, 0.83 g per kg bodyweight was used\u003csup\u003e\u003cspan citationid=\"CR39\" class=\"CitationRef\"\u003e39\u003c/span\u003e,\u003cspan citationid=\"CR40\" class=\"CitationRef\"\u003e40\u003c/span\u003e\u003c/sup\u003e, unless a higher need was recommended by the ESPEN guidelines depending on specific health conditions (e.g. after hospitalisation, in older participants or in case of sarcopenia)\u003csup\u003e\u003cspan additionalcitationids=\"CR42\" citationid=\"CR41\" class=\"CitationRef\"\u003e41\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR43\" class=\"CitationRef\"\u003e43\u003c/span\u003e\u003c/sup\u003e. The Belgian High Health Council guidelines of 50\u0026ndash;55 energy percent (En%) from carbohydrates and \u0026ge;\u0026thinsp;20 and \u0026le;\u0026thinsp;35 En% for lipids were used as guidelines for the intake of the other macronutrients\u003csup\u003e\u003cspan citationid=\"CR39\" class=\"CitationRef\"\u003e39\u003c/span\u003e\u003c/sup\u003e. Based on the body composition (high or low fat mass of fat-free mass), the dietitian decided if a caloric surplus or caloric deficit of maximally 500 kcal was necessary, and the nutritional targets were adjusted according to dietetic practice\u003csup\u003e\u003cspan citationid=\"CR35\" class=\"CitationRef\"\u003e35\u003c/span\u003e\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003eTo assess the nutritional intake, the dietitians calculated the mean daily intake from 3-day food diary using the Belgian Food Composition Database NUBEL\u003csup\u003e\u003cspan citationid=\"CR44\" class=\"CitationRef\"\u003e44\u003c/span\u003e\u003c/sup\u003e. They compared the mean daily energy and protein intake with the individual needs, and the mean daily carbohydrate and lipid intake with the guidelines from the Belgian High Health Council\u003csup\u003e\u003cspan citationid=\"CR39\" class=\"CitationRef\"\u003e39\u003c/span\u003e\u003c/sup\u003e, to assess the quality of the usual intake. The energy-feeding adequacy (EFA) was calculated as the ratio between the mean energy intake and the requirement. Based on these results and the nutritional anamnesis, the dietitians gave personalised nutritional counselling, considering both the qualitative and quantitative nutritional aspects. This was done during weekly tele-consultations with the participants between baseline and the end of the intervention period (12 weeks\u0026thinsp;\u0026plusmn;\u0026thinsp;7 days). This is a low-threshold intervention with proven benefit and feasibility\u003csup\u003e\u003cspan citationid=\"CR45\" class=\"CitationRef\"\u003e45\u003c/span\u003e\u003c/sup\u003e. As this was a pragmatic trial, the dietitians were able to use any evidence-based tool that they would use in usual, personalised care. This included dietary adjustments based on meal composition, portion sizes and frequency, education on specific product choices etc. If necessary, nutritional therapy consisting of oral supplements could be prescribed after consultation with a medical doctor within the study team.\u003c/p\u003e \u003cp\u003e \u003cem\u003ePersonalised physical exercise program.\u003c/em\u003e \u003c/p\u003e \u003cp\u003eThe exercise program followed the recommendations of the World Physiotherapy Organisation for patient-tailored physical exercise\u003csup\u003e\u003cspan citationid=\"CR46\" class=\"CitationRef\"\u003e46\u003c/span\u003e\u003c/sup\u003e. A symptom-titrated pacing strategy was implemented to account for exercise intolerance or PEM. Individuals with PEM were identified by inquiring about their symptoms and the impact of physical, cognitive, and social activities on symptoms 12 hours or longer after exertion\u003csup\u003e\u003cspan citationid=\"CR46\" class=\"CitationRef\"\u003e46\u003c/span\u003e\u003c/sup\u003e. If PEM was present, symptom stabilization was prioritized. Consequently, symptom-contingent pacing was used to guide activities based on perceived symptom levels to avoid worsening symptoms, conserve energy, and enable participation in meaningful activities. Therapists and participants focused on energy conservation and balancing activities with rest to prevent further aggravation. Progression to subsequent stages in the exercise program was based on individual measures of perceived exertion and a visual analogue scale for symptoms. Over a period of 12 weeks, participants trained a maximum of 2 to 3 times per week, with 18 sessions supervised by a trained physiotherapist. The physiotherapist's objective was to teach participants to independently plan and pace their activities of daily life and to slowly increase the training load based on individual assessments and symptoms. The program consisted of different progressive phases, including preparation for return to exercise (e.g., breathing and stretching), low-intensity activity, moderate-intensity analytical and functional exercises, and return to pre-COVID activity levels.\u003c/p\u003e \u003cp\u003e \u003cspan type=\"ItalicUnderline\" class=\"ItalicUnderline\" name=\"Emphasis\"\u003eControl intervention: standard physiotherapy.\u003c/span\u003e \u003c/p\u003e \u003cp\u003eThe participants of the control group received a maximum of 18 supervised sessions with a physiotherapist containing standard care. The participants received an information leaflet (following the World Physiotherapy Organisation recommendations) with information regarding symptom-contingent pacing to inform their physiotherapist, as well as general recommendations on healthy nutrition based on the recommendations of the Belgian High Health Council.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec7\" class=\"Section2\"\u003e \u003ch2\u003eStudy endpoints\u003c/h2\u003e \u003cp\u003eThe four study visits took place at baseline (T0), 6 weeks\u0026thinsp;\u0026plusmn;\u0026thinsp;7 days of intervention (T1), 12 weeks\u0026thinsp;\u0026plusmn;\u0026thinsp;7 days (=\u0026thinsp;end of intervention) (T2) and follow-up 6 weeks\u0026thinsp;\u0026plusmn;\u0026thinsp;7 days after end of intervention (T3).\u003c/p\u003e \u003cp\u003eThe main outcomes of the pilot were recruitment feasibility, attrition rate, intervention feasibility and study burden. Intervention feasibility consisted of the adherence to the nutritional teleconsultations, calculated as the ratio of the number of teleconsultations that were carried out versus the number of planned consultations, and the number of attended physiotherapy sessions out of the 18 prescribed sessions. The study burden was assessed by using statements C4 (\u0026ldquo;Overall, I was satisfied with my trial experience\u0026rdquo;) and C5 (\u0026ldquo;Compared to when the trial started, the overall commitment required was similar to what I expected\u0026rdquo;) of the Study Participant Feedback Questionnaire (SPFQ) (TransCelerate Biopharma Inc)\u003csup\u003e\u003cspan citationid=\"CR47\" class=\"CitationRef\"\u003e47\u003c/span\u003e\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003eBased on discussions with a patient-representative, outcomes were chosen to assess the effectiveness of the PMT. To determine the necessary sample size for a powered RCT to show an effect between the PMT and standard physiotherapy, the primary effectiveness outcome was the difference in 1-minute sit-to-stand (1-MSTS) repetitions at T2. The 1-MSTS test has been used in a multitude of populations\u003csup\u003e\u003cspan additionalcitationids=\"CR49\" citationid=\"CR48\" class=\"CitationRef\"\u003e48\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR50\" class=\"CitationRef\"\u003e50\u003c/span\u003e\u003c/sup\u003e, but few studies have been performed in the long COVID population\u003csup\u003e\u003cspan additionalcitationids=\"CR52 CR53 CR54\" citationid=\"CR51\" class=\"CitationRef\"\u003e51\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR55\" class=\"CitationRef\"\u003e55\u003c/span\u003e\u003c/sup\u003e. At the time of the design of this pilot study, no core-outcome set had been defined, so other outcomes were included to assess the effect of the PMT. The full list of outcomes can be found in the published protocol\u003csup\u003e\u003cspan citationid=\"CR33\" class=\"CitationRef\"\u003e33\u003c/span\u003e\u003c/sup\u003e. Here we describe the findings for the 6-minute walk test (6-MWT) that was used to measure physical performance, and for the Multidimensional Fatigue Inventory (MFI-20) that was used to assess fatigue. The MFI-20 scores general fatigue, physical fatigue, reduced activities, reduced motivation, and mental fatigue, with a range between 4 and 20, a higher score indicating more fatigue\u003csup\u003e\u003cspan citationid=\"CR56\" class=\"CitationRef\"\u003e56\u003c/span\u003e\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003e The baseline mean daily intake of calories (kcal per day), proteins (g per kg per day), lipids (g and En%) and carbohydrates (g and En%) are reported and compared to the guidelines. The EFA based on the TEE (EFA\u003csub\u003eTEE\u003c/sub\u003e) was calculated as the mean daily energy intake (kcal per day)/TEE (kcal per day). Additionally, the EFA based on the REE (EFA\u003csub\u003eREE\u003c/sub\u003e) was calculated as the mean daily energy intake (kcal per day)/REE (kcal per day).\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec8\" class=\"Section2\"\u003e \u003ch2\u003eStatistics and reproducibility:\u003c/h2\u003e \u003cp\u003eDescriptive analysis was performed using IBM SPSS (version 29.0.0.). To gain insight into the distribution of the effectiveness outcomes For each of effectiveness outcomes the mean, standard deviation (SD) and the 95% confidence interval (95% CI) were calculated for the within and between group changes between each follow-up study visit and the baseline assessment.\u003c/p\u003e \u003cp\u003eSample sizes were calculated using G*Power 3.1.9.2. for a large scale RCT based on the 1-MSTS, 6-MWT and physical fatigue changes after 18 weeks. We aimed for a power of .8, allowed a type II error of .05 (two-sided), and used the SD of both groups between T3 and T0 and the Pearson correlation coefficient (r) of both groups between T3 and T0 and the minimally clinically important differences (MCIDs) to define the effect sizes. For 1-MSTS, a MCID of +\u0026thinsp;3 was used\u003csup\u003e\u003cspan citationid=\"CR49\" class=\"CitationRef\"\u003e49\u003c/span\u003e\u003c/sup\u003e, for the 6-MWT a MCID of +\u0026thinsp;14 was used\u003csup\u003e\u003cspan citationid=\"CR57\" class=\"CitationRef\"\u003e57\u003c/span\u003e\u003c/sup\u003e, and for physical fatigue a MCID of -2 was used\u003csup\u003e\u003cspan citationid=\"CR58\" class=\"CitationRef\"\u003e58\u003c/span\u003e\u003c/sup\u003e.\u003c/p\u003e \u003c/div\u003e"},{"header":"Results","content":"\u003cdiv id=\"Sec10\" class=\"Section2\"\u003e \u003ch2\u003eBaseline characteristics\u003c/h2\u003e \u003cp\u003eThe mean age of the participants was 43\u0026thinsp;\u0026plusmn;\u0026thinsp;10 years, and the majority (64.6%) were female. The mean BMI was 26\u0026thinsp;\u0026plusmn;\u0026thinsp;4 kg per m\u0026sup2;. Most participants had a mild COVID-19 disease course (9.2% was hospitalised and 3.1% was admitted to the ICU). The mean duration of long COVID symptoms was 78\u0026thinsp;\u0026plusmn;\u0026thinsp;43 weeks.\u003c/p\u003e \u003cp\u003e During the 1-MSTS the participants performed 24\u0026thinsp;\u0026plusmn;\u0026thinsp;8 sit-to-stand repetitions. During the 6-MWT the participants walked 536\u0026thinsp;\u0026plusmn;\u0026thinsp;97 meters. The MFI-20 scores in the study population were right-skewed, indicating high fatigue, with 17\u0026thinsp;\u0026plusmn;\u0026thinsp;4 for general fatigue, 17\u0026thinsp;\u0026plusmn;\u0026thinsp;3 for physical fatigue, 15\u0026thinsp;\u0026plusmn;\u0026thinsp;3 for reduced activity, 12\u0026thinsp;\u0026plusmn;\u0026thinsp;3 for reduced motivation, and 14\u0026thinsp;\u0026plusmn;\u0026thinsp;4 for mental fatigue.\u003c/p\u003e \u003cp\u003eThe REE was 1823\u0026thinsp;\u0026plusmn;\u0026thinsp;365 kcal per day or 24\u0026thinsp;\u0026plusmn;\u0026thinsp;4 kcal per kg bodyweight per day. The PAL was 1.6\u0026thinsp;\u0026plusmn;\u0026thinsp;0.1, leading to a TEE of 2848\u0026thinsp;\u0026plusmn;\u0026thinsp;647. The mean daily energy intake, calculated from the 3-day food diary, was 1876\u0026thinsp;\u0026plusmn;\u0026thinsp;478. The EFA\u003csub\u003eTEE\u003c/sub\u003e was 0.69\u0026thinsp;\u0026plusmn;\u0026thinsp;0.21, and the EFA\u003csub\u003eREE\u003c/sub\u003e was 1.06\u0026thinsp;\u0026plusmn;\u0026thinsp;0.31. The mean daily carbohydrate intake was 203\u0026thinsp;\u0026plusmn;\u0026thinsp;70 g per day (43\u0026thinsp;\u0026plusmn;\u0026thinsp;7 En%). The mean daily lipid intake was 76\u0026thinsp;\u0026plusmn;\u0026thinsp;23 g per day (36\u0026thinsp;\u0026plusmn;\u0026thinsp;7 En%). The mean daily protein intake was 74\u0026thinsp;\u0026plusmn;\u0026thinsp;21 g per day (1.01\u0026thinsp;\u0026plusmn;\u0026thinsp;0.37 g per kg per day). When compared to the guidelines for nutritional needs, 48.3% had an EFA\u003csub\u003eREE\u003c/sub\u003e \u0026lt; 1, 42.8% had a protein intake\u0026thinsp;\u0026lt;\u0026thinsp;0.83 g per kg body weight, 83.1% had a carbohydrate intake\u0026thinsp;\u0026lt;\u0026thinsp;50 En%, and 65.2% had a lipid intake\u0026thinsp;\u0026gt;\u0026thinsp;35 En%.\u003c/p\u003e \u003cp\u003eDescriptives of both groups can be found in Table \u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec11\" class=\"Section2\"\u003e \u003ch2\u003eInteresting findings\u003c/h2\u003e \u003cp\u003eWhile this pilot study was not set up to have sufficient power to show any interaction between the changing effectiveness outcomes (1-MSTS, 6-MWT and MFI-20) and our experimental groups, the following sections will highlight interesting findings that can be of importance for the calculation of the sample size of future RCTs.\u003c/p\u003e \u003cp\u003eTable\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e shows the mean difference (MD) [95% Confidence Interval] in functional performance (1-MSTS and 6-MWT) and fatigue (MFI-20) throughout the different study visits, for each group. There was no significant difference in 1-MSTS repetitions at the primary endpoint (T2) between both groups as reflected by a non-significant MD of -0.97 [-3.70, 1.75] repetitions. However, the estimated effect between the groups increased over the trial duration, from a MD -0.65 [-2.95, 1.65] at T1 to -2.14 [-5.54, 1.26]) at T3. This is mainly due to an observed positive trend in the PMT group (see Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e) with significant mean differences within the PMT group ranging from a MD 2.37 [0.93, 3.81]) at T1 to 5.32 [2.94, 7.70]) at T3.\u003c/p\u003e \u003cp\u003eA similar positive trend was observed for the 6-MWT, as the estimated effect between groups increased from a MD of -5.51 [-29.1, 18.7]) at T1 to -23.99 [-59.03, 11.04]) at T3. Again, this is explained by a positive trend in the PMT group (see Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003e) with significant mean differences within the PMT group ranging from 13.65 [1.74, 25.56]) at T1 to 34.79 [15.89, 53.70] at T3.\u003c/p\u003e \u003cp\u003eFor physical fatigue, the mean difference between groups at T3 was significant, with an estimated effect of 2.21 [0.13, 4.29]). This indicates that the PMT has a beneficial effect on physical fatigue compared to standard physiotherapy. The PMT group showed a significant reduction by T3 (MD of -2.12 [-3.84, -0.40]), which was not seen in the control group (MD of 0.09 [-1.18, 1.36]).\u003c/p\u003e \u003cp\u003eFor general fatigue, reduced activity, reduced motivation, and mental fatigue no significant changes were observed within either group across all study visits. No significant between-group difference was observed. However, a growing effect within the PMT group was observed (see Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003e), which was near significance for general fatigue (MD of -1.28 [-2.59, 0.03]), reduced activity (MD of-1.48 [-2.96, 0.00]) and mental fatigue (MD of -1.44 [-2.93, 0.05]) at T3.\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab1\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eBaseline characteristics\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"4\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eTotal sample\u003c/p\u003e \u003cp\u003e(n\u0026thinsp;=\u0026thinsp;65)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eControl group\u003c/p\u003e \u003cp\u003e(n\u0026thinsp;=\u0026thinsp;33)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003ePMT group\u003c/p\u003e \u003cp\u003e(n\u0026thinsp;=\u0026thinsp;32)\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePopulation characteristics\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSex (% female)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e64.6\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e63.6\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e65.6\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAge (years) (mean\u0026thinsp;\u0026plusmn;\u0026thinsp;SD)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e43\u0026thinsp;\u0026plusmn;\u0026thinsp;10\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e44\u0026thinsp;\u0026plusmn;\u0026thinsp;11\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e43\u0026thinsp;\u0026plusmn;\u0026thinsp;11\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSmoking (% yes)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e4.6\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e9.1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.0\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eHospitalised during COVID-19 (% yes)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e9.2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e9.1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e9.4\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eLength of hospitalisation (mean\u0026thinsp;\u0026plusmn;\u0026thinsp;SD)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e16\u0026thinsp;\u0026plusmn;\u0026thinsp;18\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e19\u0026thinsp;\u0026plusmn;\u0026thinsp;24\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e13\u0026thinsp;\u0026plusmn;\u0026thinsp;15\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAdmitted to ICU (% yes)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e3.1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e3.0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e3.1\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eLength of ICU admission (days) (mean\u0026thinsp;\u0026plusmn;\u0026thinsp;SD)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e20\u0026thinsp;\u0026plusmn;\u0026thinsp;16\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e31\u0026thinsp;\u0026plusmn;\u0026thinsp;0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e9\u0026thinsp;\u0026plusmn;\u0026thinsp;0\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eLong COVID duration (weeks) (mean\u0026thinsp;\u0026plusmn;\u0026thinsp;SD)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e78\u0026thinsp;\u0026plusmn;\u0026thinsp;43\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e81\u0026thinsp;\u0026plusmn;\u0026thinsp;44\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e75\u0026thinsp;\u0026plusmn;\u0026thinsp;42\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eBody Mass Index (kg/m\u0026sup2;)(mean\u0026thinsp;\u0026plusmn;\u0026thinsp;SD)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e26\u0026thinsp;\u0026plusmn;\u0026thinsp;4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e26\u0026thinsp;\u0026plusmn;\u0026thinsp;4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e25\u0026thinsp;\u0026plusmn;\u0026thinsp;4\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eFunctional performance\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e1-MSTS repetitions (mean\u0026thinsp;\u0026plusmn;\u0026thinsp;SD)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e24\u0026thinsp;\u0026plusmn;\u0026thinsp;8\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e24\u0026thinsp;\u0026plusmn;\u0026thinsp;10\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e24\u0026thinsp;\u0026plusmn;\u0026thinsp;6\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e6-MWT (meters)(mean\u0026thinsp;\u0026plusmn;\u0026thinsp;SD)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e536\u0026thinsp;\u0026plusmn;\u0026thinsp;97\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e531\u0026thinsp;\u0026plusmn;\u0026thinsp;114\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e542\u0026thinsp;\u0026plusmn;\u0026thinsp;76\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eFatigue\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eGeneral fatigue (mean\u0026thinsp;\u0026plusmn;\u0026thinsp;SD)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e17\u0026thinsp;\u0026plusmn;\u0026thinsp;4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e16\u0026thinsp;\u0026plusmn;\u0026thinsp;4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e17\u0026thinsp;\u0026plusmn;\u0026thinsp;3\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePhysical fatigue (mean\u0026thinsp;\u0026plusmn;\u0026thinsp;SD)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e17\u0026thinsp;\u0026plusmn;\u0026thinsp;3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e17\u0026thinsp;\u0026plusmn;\u0026thinsp;3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e17\u0026thinsp;\u0026plusmn;\u0026thinsp;3\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eReduced activity (mean\u0026thinsp;\u0026plusmn;\u0026thinsp;SD)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e15\u0026thinsp;\u0026plusmn;\u0026thinsp;3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e14\u0026thinsp;\u0026plusmn;\u0026thinsp;3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e16\u0026thinsp;\u0026plusmn;\u0026thinsp;3\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eReduced motivation (mean\u0026thinsp;\u0026plusmn;\u0026thinsp;SD)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e12\u0026thinsp;\u0026plusmn;\u0026thinsp;3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e12\u0026thinsp;\u0026plusmn;\u0026thinsp;3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e12\u0026thinsp;\u0026plusmn;\u0026thinsp;3\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMental fatigue (mean\u0026thinsp;\u0026plusmn;\u0026thinsp;SD)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e14\u0026thinsp;\u0026plusmn;\u0026thinsp;4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e15\u0026thinsp;\u0026plusmn;\u0026thinsp;4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e14\u0026thinsp;\u0026plusmn;\u0026thinsp;4\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eNutritional parameters\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eREE\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ekcal/day (mean\u0026thinsp;\u0026plusmn;\u0026thinsp;SD)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1823\u0026thinsp;\u0026plusmn;\u0026thinsp;365\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1802\u0026thinsp;\u0026plusmn;\u0026thinsp;364\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1845\u0026thinsp;\u0026plusmn;\u0026thinsp;370\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ekcal/kg/day (mean\u0026thinsp;\u0026plusmn;\u0026thinsp;SD)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e24\u0026thinsp;\u0026plusmn;\u0026thinsp;4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e24\u0026thinsp;\u0026plusmn;\u0026thinsp;3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e24\u0026thinsp;\u0026plusmn;\u0026thinsp;4\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePAL (mean\u0026thinsp;\u0026plusmn;\u0026thinsp;SD)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1.6\u0026thinsp;\u0026plusmn;\u0026thinsp;0.1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1.6\u0026thinsp;\u0026plusmn;\u0026thinsp;0.1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1.6\u0026thinsp;\u0026plusmn;\u0026thinsp;0.1\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eTEE (mean\u0026thinsp;\u0026plusmn;\u0026thinsp;SD)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e2848\u0026thinsp;\u0026plusmn;\u0026thinsp;647\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e2812\u0026thinsp;\u0026plusmn;\u0026thinsp;704\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e2888\u0026thinsp;\u0026plusmn;\u0026thinsp;588\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eEnergy intake (kcal/day) (mean\u0026thinsp;\u0026plusmn;\u0026thinsp;SD)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1876\u0026thinsp;\u0026plusmn;\u0026thinsp;478\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1860\u0026thinsp;\u0026plusmn;\u0026thinsp;483\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1892\u0026thinsp;\u0026plusmn;\u0026thinsp;479\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eEFA\u003csub\u003eTEE\u003c/sub\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0.69\u0026thinsp;\u0026plusmn;\u0026thinsp;0.21\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.69\u0026thinsp;\u0026plusmn;\u0026thinsp;0.22\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.68\u0026thinsp;\u0026plusmn;\u0026thinsp;0.2\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eEFA\u003csub\u003eREE\u003c/sub\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1.06\u0026thinsp;\u0026plusmn;\u0026thinsp;0.31\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1.07\u0026thinsp;\u0026plusmn;\u0026thinsp;0.31\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1.05\u0026thinsp;\u0026plusmn;\u0026thinsp;0.32\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCarbohydrate intake\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eg/day (mean\u0026thinsp;\u0026plusmn;\u0026thinsp;SD)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e203\u0026thinsp;\u0026plusmn;\u0026thinsp;70\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e206\u0026thinsp;\u0026plusmn;\u0026thinsp;68\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e200\u0026thinsp;\u0026plusmn;\u0026thinsp;74\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eEn% (mean\u0026thinsp;\u0026plusmn;\u0026thinsp;SD)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e43\u0026thinsp;\u0026plusmn;\u0026thinsp;7\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e44\u0026thinsp;\u0026plusmn;\u0026thinsp;5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e42\u0026thinsp;\u0026plusmn;\u0026thinsp;8\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eLipid intake\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eg/day (mean\u0026thinsp;\u0026plusmn;\u0026thinsp;SD)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e76\u0026thinsp;\u0026plusmn;\u0026thinsp;23\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e74\u0026thinsp;\u0026plusmn;\u0026thinsp;22\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e78\u0026thinsp;\u0026plusmn;\u0026thinsp;23\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eEn% (mean\u0026thinsp;\u0026plusmn;\u0026thinsp;SD)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e36\u0026thinsp;\u0026plusmn;\u0026thinsp;7\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e36\u0026thinsp;\u0026plusmn;\u0026thinsp;6\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e37\u0026thinsp;\u0026plusmn;\u0026thinsp;7\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eProtein intake\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eg/day (mean\u0026thinsp;\u0026plusmn;\u0026thinsp;SD)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e74\u0026thinsp;\u0026plusmn;\u0026thinsp;21\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e72\u0026thinsp;\u0026plusmn;\u0026thinsp;21\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e75\u0026thinsp;\u0026plusmn;\u0026thinsp;21\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eg/kg/day (mean\u0026thinsp;\u0026plusmn;\u0026thinsp;SD)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1.01\u0026thinsp;\u0026plusmn;\u0026thinsp;0.37\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.99\u0026thinsp;\u0026plusmn;\u0026thinsp;0.33\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1.03\u0026thinsp;\u0026plusmn;\u0026thinsp;0.4\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003eValues are shown as mean (standard error (SD)) or % yes. 1-MSTS: one-minute sit-to-stand; 6-MWT: six-minute walk test; EFA\u003csub\u003eREE\u003c/sub\u003e: energy-feeding adequacy based on the Resting Energy Expenditure (REE); EFA\u003csub\u003eTEE\u003c/sub\u003e: energy-feeding adequacy based on the Total Energy Expenditure (TEE); En%: energy percent; PAL: physical activity level; PMT: personalized multimodal treatment.\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab2\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 2\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eMean changes in functional performance and fatigue\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"6\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c6\" colnum=\"6\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colspan=\"2\" nameend=\"c3\" namest=\"c2\"\u003e \u003cp\u003eControl group\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colspan=\"2\" nameend=\"c5\" namest=\"c4\"\u003e \u003cp\u003ePMT group\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c6\"\u003e \u003cp\u003eMean difference\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003en\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003emean [95% CI]\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003en\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003emean [95% CI]\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c6\"\u003e \u003cp\u003emean [95% CI]\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003e1-MSTS\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eChange between T1 and T0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e25\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1.72 [-0.14, 3.58]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e27\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e2.37 [0.93, 3.81]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e-0.65 [-2.95, 1.65]\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eChange between T2 and T0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e22\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e2.55 [0.27, 4.82]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e27\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e3.52 [1.9, 5.14]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e-0.97 [-3.7, 1.75]\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eChange between T3 and T0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e22\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e3.18 [0.62, 5.74]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e25\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e5.32 [2.94, 7.70]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e-2.14 [-5.54, 1.26]\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003e6-MWT\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eChange between T1 and T0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e25\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e8.14[ -12.74, 29.02]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e26\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e13.65 [1.74, 25.56]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e-5.51 [-29.1, 18.07]\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eChange between T2 and T0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e22\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e3.75[ -25.56, 33.06]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e27\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e21.26 [5.13, 37.39]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e-17.51 [-50.31, 15.29]\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eChange between T3 and T0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e22\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e10.8[ -19.67, 41.26]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e24\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e34.79 [15.89, 53.70]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e-23.99 [-59.03, 11.04]\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eGeneral fatigue\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eChange between T1 and T0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e26\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e-0.31 [-1.68, 1.06]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e29\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e-0.14 [-1.69, 1.42]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e-0.17 [-2.19, 1.85]\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eChange between T2 and T0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e22\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e-0.64 [-3.17, 1.90]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e27\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e-0.22 [-1.4, 0.95]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e-0.42 [-3.16, 2.34]\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eChange between T3 and T0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e22\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.18 [-2.36, 2.72]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e25\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e-1.28 [-2.59, 0.03]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e1.46 [-1.34, 4.27]\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003ePhysical fatigue\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eChange between T1 and T0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e25\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e-0.52 [-1.71, 0.67]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e29\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e-0.83 [-2.48, 0.83]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0.31 [-1.69, 2.30]\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eChange between T2 and T0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e22\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e-0.27 [-1.66, 1.12]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e27\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e-0.78 [-1.91, 0.36]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0.51 [-1.24, 2.25]\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eChange between T3 and T0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e22\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.09 [-1.18, 1.36]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e25\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e-2.12 [-3.84, -0.40]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e2.21 [0.13, 4.29]\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eReduced activity\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eChange between T1 and T0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e25\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.92 [-0.32, 2.16]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e29\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e-0.34 [-1.48, 0.79]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e1.26 [-0.38, 2.91]\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eChange between T2 and T0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e22\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e-0.32 [-1.47, 0.84]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e27\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e-0.15 [-1.59, 1.29]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e-0.17 [-1.97, 1.63]\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eChange between T3 and T0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e22\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e-0.45 [-1.77, 0.86]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e25\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e-1.48 [-2.96, 0.00]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e1.03 [-0.91, 2.96]\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eReduced motivation\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eChange between T1 and T0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e25\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.36 [-1.62, 2.34]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e29\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.62 [-0.50, 1.75]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e-0.26 [-2.50, 1.98]\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eChange between T2 and T0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e22\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e-0.09 [-2.08, 1.90]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e27\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e-0.48 [-1.77, 0.81]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0.39 [-1.93, 2.71]\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eChange between T3 and T0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e22\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.41 [-1.61, 2.43]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e25\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e-0.76 [-2.03, 0.51]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e1.17 [-1.16, 3.5]\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eMental fatigue\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eChange between T1 and T0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e25\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e-0.44 [-1.93, 1.05]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e29\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.31 [-0.93, 1.55]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e-0.75 [-2.64, 1.14]\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eChange between T2 and T0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e22\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e-0.05 [-2.05, 1.96]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e27\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.19 [-1.1, 1.47]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e-0.24 [-2.56, 2.1]\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eChange between T3 and T0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e22\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.14 [-1.73, 2.00]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e25\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e-1.44 [-2.93, 0.05]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e1.58 [-0.75, 3.9]\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003eValues are shown as mean [95% Confidence Interval]. 1-MSTS: one-minute sit-to-stand; 6-MWT: six-minute walk test.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec12\" class=\"Section2\"\u003e \u003ch2\u003eFeasibility\u003c/h2\u003e \u003cp\u003eIn total, 141 individuals were assessed for eligibility of which 65 were included (see Fig.\u0026nbsp;\u003cspan refid=\"Fig5\" class=\"InternalRef\"\u003e5\u003c/span\u003e). Recruitment took 16 months (average 9 per month). The attrition was 18.5% at T1, 24.6% at T2 and 27.7% at T3. The study and the PMT was considered comparable to that of standard of care. One medically significant event was reported (one participant was admitted to the emergency care), but no causality between the study intervention was suspected. Participants in the PMT group had 10\u0026thinsp;\u0026plusmn;\u0026thinsp;4 teleconsultations with the dietitian (range: 0\u0026ndash;13). Average adherence to the nutritional counselling sessions was 0.83\u0026thinsp;\u0026plusmn;\u0026thinsp;0.28. However, in the participants who had an early trial termination, the adherence was 0.45\u0026thinsp;\u0026plusmn;\u0026thinsp;0.39. Participants received 14\u0026thinsp;\u0026plusmn;\u0026thinsp;4 and 13\u0026thinsp;\u0026plusmn;\u0026thinsp;5 physiotherapy sessions in the PMT and control group respectively during the interventional period. Additionally, 77.1% of participants who completed the trial indicated that they continued the intervention after T2. Figure\u0026nbsp;\u003cspan refid=\"Fig4\" class=\"InternalRef\"\u003e4\u003c/span\u003e shows the participant study burden results.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec13\" class=\"Section2\"\u003e \u003ch2\u003eSample size calculations\u003c/h2\u003e \u003cp\u003eAs discussed in a previous section, the estimated effect between groups increased over the trial duration for the 1-MSTS, 6-MWT and MFI-20. This indicates that extending the intervention period from 12 weeks to 18 weeks is more beneficial. Based on these results, the SD and r for all effectiveness outcomes were calculated for the mean change between T3 and T0 (1-MSTS: SD\u0026thinsp;=\u0026thinsp;8.18, r\u0026thinsp;=\u0026thinsp;0.78; 6-MWT: SD\u0026thinsp;=\u0026thinsp;92.2, r\u0026thinsp;=\u0026thinsp;0.82; physical fatigue: SD: 3.05, r\u0026thinsp;=\u0026thinsp;0.53). Using these parameters and the observed data distribution from this pilot study, the required sample sizes to achieve the minimally clinically important difference (MCID) between the PMT group and the control group are estimated to be 32 participants for the 1-MSTS, 142 Participants for the 6-MWT, and 29 participants for the physical fatigue measure. Taking into account the attrition rate of 27.7% at T3, a total sample size of 181 participants should be recruited for RCT.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003c/div\u003e"},{"header":"Discussion","content":"\u003cp\u003eWe hypothesised that a personalised multimodal treatment (PMT), consisting of personalised nutritional counselling and physiotherapy would provide a synergistic effect, offering a comprehensive strategy to manage fatigue and improve the physical performance of individuals with long COVID. This pilot pragmatic randomized controlled trial examined the feasibility of the PMT, as well as the effectiveness compared to standard physiotherapy alone.\u003c/p\u003e \u003cp\u003ePositive effects were seen on physical performance outcome parameters, the 1-MSTS and the 6-MWT (see Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e and Figs.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e\u0026ndash;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003e). The mean results in the study population at baseline were low compared to reference values in healthy adults\u003csup\u003e\u003cspan citationid=\"CR59\" class=\"CitationRef\"\u003e59\u003c/span\u003e,\u003cspan citationid=\"CR60\" class=\"CitationRef\"\u003e60\u003c/span\u003e\u003c/sup\u003e, but were similar to those found in other post-COVID studies\u003csup\u003e\u003cspan additionalcitationids=\"CR52 CR53 CR54\" citationid=\"CR51\" class=\"CitationRef\"\u003e51\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR55\" class=\"CitationRef\"\u003e55\u003c/span\u003e\u003c/sup\u003e. Although we did not find a significant effect for the performance outcomes between the intervention groups, both 1-MSTS and 6-MWT improved within the PMT group, while the improvement was not seen in the control group. For the 1-MSTS, the Minimal Clinically Important Difference (MCID) of +\u0026thinsp;3 repetitions based on the Chronic Obstructive Pulmonary Disease (COPD) population\u003csup\u003e\u003cspan citationid=\"CR49\" class=\"CitationRef\"\u003e49\u003c/span\u003e\u003c/sup\u003e was reached after 12 weeks and continued to improve. For the 6-MWT, the smallest MCID of 14 meters\u003csup\u003e\u003cspan citationid=\"CR57\" class=\"CitationRef\"\u003e57\u003c/span\u003e\u003c/sup\u003e was nearly reached in the PMT after 6 weeks, while it was not reached in the control group, even after 18 weeks. Zheng et al. also showed these positive effects of physical rehabilitation intervention on exercise capacity (effect size estimate for 6-MWT of 94.76 (14.83 to 174.70) and 1-MSTS of 0.54 (-0.13 to 1.22) and fatigue (effect size estimate 0.57 (0.15 to 0.98) [32]. However, the evidence remains uncertain because of low quality studies with high risk of bias\u003csup\u003e\u003cspan citationid=\"CR31\" class=\"CitationRef\"\u003e31\u003c/span\u003e,\u003cspan citationid=\"CR32\" class=\"CitationRef\"\u003e32\u003c/span\u003e,\u003cspan citationid=\"CR61\" class=\"CitationRef\"\u003e61\u003c/span\u003e\u003c/sup\u003e. A possible reason could be the heterogenicity of the physical rehabilitation interventions: breathing exercises either alone or in combination with resistance and/or aerobic training, only aerobic training or in combination with strengthening, stretching, motor or balance training etc. Interventions were all compared with usual care in the form of respiratory training and exercises-based, self-management education. This is a big difference with our study were the control group received supervised physiotherapy sessions with some additional advice such as breathing exercises and pacing, and the PMT group received the additional nutritional counselling to support the physical rehabilitation.\u003c/p\u003e \u003cp\u003eOne of the foundational principles of this study is the concept of combined nutrition and physiotherapy in the context of long COVID management. Exercise and nutrition plans were tailored based on each patient's specific individual symptoms and nutritional adequacy, respectively. This approach aligns with the growing recognition that long COVID presents with a highly variable symptomatology\u003csup\u003e\u003cspan additionalcitationids=\"CR7 CR8 CR9\" citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e\u003c/sup\u003e, necessitating customized treatment plans. By evaluating individual metabolic rates and dietary preferences, the personalized program aimed to optimize energy levels and promote muscle recovery more effectively than standard physiotherapy alone. Traditional physiotherapy does not typically integrate dietary management, potentially overlooking an essential aspect of recovery. Our study is the first to report the results of a multidisciplinary rehabilitation program including both nutritional and physical rehabilitation in individuals with a longer duration of long COVID, and with a variety of COVID-19 disease history, of which the majority was not hospitalized. The positive effect of nutritional intervention was also found by Gobbi et al. who performed a 28-day long multidisciplinary intervention including nutritional therapy based on the ESPEN guidelines in post-acute COVID-19 patients after discharge\u003csup\u003e\u003cspan citationid=\"CR62\" class=\"CitationRef\"\u003e62\u003c/span\u003e\u003c/sup\u003e. This highlights the need for a comprehensive nutritional intervention in the post-acute phase of the recovery\u003csup\u003e\u003cspan citationid=\"CR62\" class=\"CitationRef\"\u003e62\u003c/span\u003e\u003c/sup\u003e. Dietary interventions in the long COVID population generally focus on nutritional supplements, even when nutrition is proposed as part of a multidisciplinary approach\u003csup\u003e\u003cspan additionalcitationids=\"CR64 CR65 CR66 CR67 CR68\" citationid=\"CR63\" class=\"CitationRef\"\u003e63\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR69\" class=\"CitationRef\"\u003e69\u003c/span\u003e\u003c/sup\u003e. The evidence from these studies is insufficient to propose specific nutritional supplements as treatments for long COVID. Even in similar conditions to long COVID, such as Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) or fibromyalgia, dietary interventions usually consist of nutritional supplements\u003csup\u003e\u003cspan citationid=\"CR70\" class=\"CitationRef\"\u003e70\u003c/span\u003e,\u003cspan citationid=\"CR71\" class=\"CitationRef\"\u003e71\u003c/span\u003e\u003c/sup\u003e. While there are no specific long COVID-dietary guidelines, the recommendations for energy, macronutrient and micronutrient intake in individuals recovering from a SARS-CoV-2 infection fit within evidence-based dietetic practice\u003csup\u003e\u003cspan citationid=\"CR43\" class=\"CitationRef\"\u003e43\u003c/span\u003e,\u003cspan citationid=\"CR72\" class=\"CitationRef\"\u003e72\u003c/span\u003e\u003c/sup\u003e. By opting for counselling by a dietitian, individuals learn how to adhere to the nutritional recommendations whilst making changes that are compatible with their long COVID symptoms. Personalized nutrition is an evidence-based approach that uses additional individual data (such as anthropometric, biochemical, metabolic data), to tailor general population-based interventions to each patient\u003csup\u003e\u003cspan citationid=\"CR73\" class=\"CitationRef\"\u003e73\u003c/span\u003e\u003c/sup\u003e. The complexity of personalization may cause difficulty in the reproducibility of study results. However, especially in long COVID, a one-size-fits-all approach is insufficient, due to the heterogeneity of the population\u003csup\u003e\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003eA strength of this study is the involvement of a patient representative during the conceptualisation of the protocol and as a committee member throughout the study. Another notable strength of our study is the use of indirect calorimetry (IC) to measure REE for personalized nutritional counselling in long COVID patients, offering a more accurate determination of energy requirements compared to predictive equations, which can overestimate REE by more than 900 kcal per day\u003csup\u003e\u003cspan citationid=\"CR74\" class=\"CitationRef\"\u003e74\u003c/span\u003e\u003c/sup\u003e. Previous studies have applied this method to hospitalized and critically ill COVID-19 patients during hospitalization\u003csup\u003e\u003cspan additionalcitationids=\"CR76 CR77 CR78\" citationid=\"CR75\" class=\"CitationRef\"\u003e75\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR79\" class=\"CitationRef\"\u003e79\u003c/span\u003e\u003c/sup\u003e, and to non-hospitalized COVID-19 patients before and after the acute SARS-CoV-2 infection\u003csup\u003e\u003cspan citationid=\"CR74\" class=\"CitationRef\"\u003e74\u003c/span\u003e\u003c/sup\u003e. However, to our knowledge, our study is the first to report the use of IC to determine the energy requirements of individuals with long COVID. A limitation of using indirect calorimetry in mobile individuals is that their daily energy requirements are not solely based on their REE, as in bedridden or critically ill patients, but also depend significantly on the energy expenditure during their daily physical activities. Therefore, we adhered to guidelines to estimate the TEE by multiplying the REE with a physical activity factor \u003csup\u003e\u003cspan citationid=\"CR38\" class=\"CitationRef\"\u003e38\u003c/span\u003e,\u003cspan citationid=\"CR39\" class=\"CitationRef\"\u003e39\u003c/span\u003e\u003c/sup\u003e. However, a limitation arises from the potential overestimation of Physical Activity Level (PAL) values, affecting the calculation of Total Energy Expenditure (TEE). In this study, the EFA\u003csub\u003eTEE\u003c/sub\u003e was 0.69, indicating that the participants generally had caloric deficit of almost 30%. Based on the nutritional assessments by the dietitians (e.g. weight evolution, nutritional anamnesis), the study team concluded that the PAL values recommended by the Belgian High Health council may not accurately reflect the energy expenditure of mobile individuals. Despite the potential overestimation of PAL, the results still indicate a low energy feeding adequacy when comparing mean daily energy intake with measured daily REE. At baseline, almost half of the participants (48.3%) had an EFA\u003csub\u003eREE\u003c/sub\u003e \u0026lt; 1, meaning that their nutritional intake did not cover the resting energy expenditure, let alone any additional physical activity. Additionally, 42.8% consumed less proteins that the minimally recommended dose of 0.83g per kg body weight. Most participants consumed less carbohydrates and more lipids than recommended by the High Health Council. We can conclude that the nutritional intake of a significant part of the study population at baseline was disbalanced in macronutrient intake and the total energy intake was insufficient. While using nutritional diaries to calculate daily intake is susceptible to various biases\u0026mdash;such as social desirability bias (e.g., underreporting foods perceived as \u0026ldquo;unhealthy\u0026rdquo; or overreporting foods perceived as \u0026ldquo;healthy\u0026rdquo;), inaccurate estimations of portion sizes, and omissions of ingredients\u0026mdash;the findings still highlight significant gaps in meeting energy requirements. The results from this study confirm that nutritional optimization is a potential target for the management of long COVID symptoms and emphasize the need for nutritional counselling by a registered dietitian as part of a multidisciplinary team. Future research should utilize more precise methods, such as accelerometer devices \u003csup\u003e\u003cspan citationid=\"CR80\" class=\"CitationRef\"\u003e80\u003c/span\u003e\u003c/sup\u003e in combination with indirect calorimetry, to measure physical activity energy expenditure and determine daily TEE more accurately. Additionally, longitudinal studies that examine the changes in PAL and TEE over time in long COVID patients could enhance the accuracy of energy requirement estimations.\u003c/p\u003e \u003cp\u003eOverall, the intervention was found feasible. Future studies with this intervention should consider a higher attrition, depending on the length of the intervention (almost 25% after 12 weeks, almost 28% after 18 weeks). Based on the data gathered in this study, the (expected) study burden was an important limiting factor in both recruitment and attrition (see Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e). On the other hand, participants who completed the trial indicated that although the study burden was high, they were satisfied with their trial experience (see Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003e). Additionally, the intervention-specific procedures, i.e. the teleconsultations with the dietitian and the physiotherapy sessions, were considered feasible. The data from this pilot can help address the concern for the study burden, which could potentially facilitate the recruitment of participants for a larger scale RCT. While this pilot study was not set up to have sufficient power to show any interaction between the changing effectiveness outcomes (1-MSTS, 6-MWT and MFI-20) and our experimental groups, a visualization does reveal very promising results (see Figs.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e to \u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003e). The individual evolutions themselves show a consistent pattern, which would help to uncover treatment effects in future studies. Some patients nevertheless show very different patterns, and with additional data in a larger scale RCT it will be possible to further focus on how patients differ in their evolution.\u003c/p\u003e \u003cp\u003eGenerally, the study revealed a positive trend for improved physical performance and reduced fatigue in the PMT group, that was not observed in the control group, with benefits especially persisting after the program's conclusion at 12 weeks. This indicates that a longer interventional period of at least 18 weeks is preferable. These are hopeful results, as the combined positive effect of reduced fatigue, combined with an increased physical performance after the PMT could be a therapeutic target to help manage long COVID symptoms like fatigue and PEM. To demonstrate these promising results, an RCT is needed with a sample size of 181 participants.\u003c/p\u003e"},{"header":"Declarations","content":"\u003ch2\u003eAcknowledgements:\u003c/h2\u003e \u003cp\u003eThe Belgian Healthcare Knowledge Centre (KCE) funded this study under the KCE Trials Long COVID call (LCOV-211306). We like to thank Mme Ann Li, chair of the \u0026ldquo;\u003cem\u003epost-COVID gemeenschap\u003c/em\u003e\u0026rdquo; for her advice as patient representative of this trial. We like to thank Dr. Marc Schiltz, Ann De Smet, Koen Putman, Joy Demol and Janne Geers for their contribution to the conceptualisation of the original protocol. They have been credited authorship in the published protocol.\u003c/p\u003e \u003cp\u003e\u003cspan type=\"BoldUnderline\" class=\"BoldUnderline\" name=\"Emphasis\"\u003eAutor contributions\u003c/span\u003e: Conceptualisation: B.G.J.G., S.R., L.L., D.B. and E.D.W. Formal analysis and visualisation: W.C. Preparation of the manuscript: B.G.J.G. Revision and editing of the manuscript: S.R., L.L., D.B., W.C. and E.D.W.. Supervision: D.B. and E.D.W. All authors confirm that they have read and approved the final version of the manuscript.\u003c/p\u003e\u003ch2\u003eData availability:\u003c/h2\u003e \u003cp\u003eAll data supporting the findings in this study are available through OSF registries with the identifier \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.17605/OSF.IO/86JVU\u003c/span\u003e\u003cspan address=\"10.17605/OSF.IO/86JVU\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003e\u003cem\u003eWHO Coronavirus (COVID-19) Dashboard\u003c/em\u003e, \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e\u0026lt;https://covid19.who.int/\u0026gt;\u003c/span\u003e\u003cspan address=\"http://%3Chttps://covid19.who.int/%3E\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e (\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003e(World Health Organization).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eAl-Aly, Z. \u003cem\u003eet al.\u003c/em\u003e Long COVID science, research and policy. 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Clin Nutr ESPEN 44, 211\u0026ndash;217 (2021). \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org:10.1016/j.clnesp.2021.06.016\u003c/span\u003e\u003cspan address=\"https://doi.org:10.1016/j.clnesp.2021.06.016\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eWhittle, J., Molinger, J., MacLeod, D., Haines, K. \u0026amp; Wischmeyer, P. E. Persistent hypermetabolism and longitudinal energy expenditure in critically ill patients with COVID-19. Crit Care 24, 581 (2020). \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org:10.1186/s13054-020-03286-7\u003c/span\u003e\u003cspan address=\"https://doi.org:10.1186/s13054-020-03286-7\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eWu, W. J., Yu, H. B., Tai, W. H., Zhang, R. \u0026amp; Hao, W. Y. Validity of Actigraph for Measuring Energy Expenditure in Healthy Adults: A Systematic Review and Meta-Analysis. Sensors (Basel) 23 (2023). \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org:10.3390/s23208545\u003c/span\u003e\u003cspan address=\"https://doi.org:10.3390/s23208545\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"nature-portfolio","isNatureJournal":true,"hasQc":false,"allowDirectSubmit":false,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"","title":"Nature Portfolio","twitterHandle":"","acdcEnabled":false,"dfaEnabled":false,"editorialSystem":"ejp","reportingPortfolio":"","inReviewEnabled":true,"inReviewRevisionsEnabled":false},"keywords":"","lastPublishedDoi":"10.21203/rs.3.rs-4914245/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-4914245/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003eBackground\u003c/h2\u003e \u003cp\u003eLong COVID is a multisystemic condition with debilitating symptoms, including fatigue and post-exertional malaise. Personalised nutritional counselling and physiotherapy could provide a synergistic effect to alleviate these symptoms. However, there is a lack of evidence of the feasibility and effectiveness of such personalised multimodal therapy (PMT) including both nutrition and physiotherapy.\u003c/p\u003e\u003ch2\u003eMethods\u003c/h2\u003e \u003cp\u003eIn this pilot study, 65 participants were randomised into either standard physiotherapy or the PMT. Nutritional counselling focussed on tailoring the energy and protein intake to the individual needs based on indirect calorimetry and nutritional assessments. Personalised physiotherapy focused on symptom-contingent pacing. The aim was to evaluate the feasibility in light of a randomised controlled trial (RCT) and to assess the effectiveness of the PMT compared to standard physiotherapy. Effectiveness outcomes (1-minute sit-to-stand test (1-MSTS), 6-minute walk test (6-MWT), and the Multidimensional Fatigue Inventory (MFI-20)) were assessed after 6, 12 and 18 weeks. Descriptive statistics and sample size calculations were performed.\u003c/p\u003e\u003ch2\u003eResults\u003c/h2\u003e \u003cp\u003eWe observed an advancement in both groups, however, the PMT group showed a significant improvement, for 1-MST, 6-MWT and physical fatigue at 18 weeks. Participant specific trajectories suggest a growing estimated difference between groups throughout the trial. To prove these interesting finding, 181 participants should be recruited in a RCT. Study feasibility was proven.\u003c/p\u003e\u003ch2\u003eConclusions\u003c/h2\u003e \u003cp\u003eThe study revealed a positive trend for improved physical function and reduced fatigue in adults with long COVID after combined nutritional counselling and physiotherapy. A large-scale RCT is needed to prove the effectiveness, but the current results are hopeful.\u003c/p\u003e","manuscriptTitle":"Increased physical performance and reduced fatigue after personalised physiotherapy and nutritional counselling in long COVID","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2024-12-10 06:00:19","doi":"10.21203/rs.3.rs-4914245/v1","editorialEvents":[],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"communications-medicine","isNatureJournal":true,"hasQc":false,"allowDirectSubmit":false,"externalIdentity":"commsmed","sideBox":"Learn more about [Communications Medicine](http://www.nature.com/commsmed)","snPcode":"43856","submissionUrl":"https://mts-commsmed.nature.com/cgi-bin/main.plex","title":"Communications Medicine","twitterHandle":"@commsmedicine","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"ejp","reportingPortfolio":"Communications Series","inReviewEnabled":true,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"051a80e3-8cf4-4c94-8c16-88aebc921ca9","owner":[],"postedDate":"December 10th, 2024","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[{"id":39961709,"name":"Health sciences/Medical research/Clinical trial design/Randomized controlled trials"},{"id":39961710,"name":"Health sciences/Health care/Therapeutics/Nutrition therapy"},{"id":39961711,"name":"Health sciences/Health care/Therapeutics/Rehabilitation"}],"tags":[],"updatedAt":"2026-04-14T07:06:06+00:00","versionOfRecord":{"articleIdentity":"rs-4914245","link":"https://doi.org/10.1038/s43856-026-01486-w","journal":{"identity":"communications-medicine","isVorOnly":false,"title":"Communications Medicine"},"publishedOn":"2026-03-03 05:00:00","publishedOnDateReadable":"March 3rd, 2026"},"versionCreatedAt":"2024-12-10 06:00:19","video":"","vorDoi":"10.1038/s43856-026-01486-w","vorDoiUrl":"https://doi.org/10.1038/s43856-026-01486-w","workflowStages":[]},"version":"v1","identity":"rs-4914245","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-4914245","identity":"rs-4914245","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}